Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure

Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure Abstract Background If HIV patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is crushed and dissolved prior to administration. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq®, referred to as TRI); therefore, crushing of TRI is not recommended. Objectives To investigate whether the TRI fixed-dose combination tablet can be crushed and combined with enteral nutrition without influencing pharmacokinetics (PK). Methods We carried out an open-label, three-period, randomized, single-dose, crossover trial in 22 healthy adult volunteers. Subjects randomly received whole-tablet TRI with fasting (reference), crushed and suspended TRI with fasting or crushed and suspended TRI with oral intake of enteral nutrition. Bioequivalence criteria (80%–125% acceptance range) of AUC0-∞ and Cmax were used. ClinicalTrials.gov: NCT02569346. Results Crushing TRI leads to higher dolutegravir exposure (AUC0-∞: +26% and Cmax: +30%) and, if crushed TRI is combined with enteral nutrition, to a decrease in abacavir Cmax (−17%). Lamivudine concentrations were not affected as geometric mean ratios with 90% CIs fell within the 80%–125% range. Conclusions Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition. Introduction The HIV-1 integrase inhibitor dolutegravir is marketed as a single tablet (Tivicay®) and in a fixed-dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as TRI). TRI is the largest currently available once-daily fixed-dose combination tablet, possibly causing adherence issues in young adolescents and in patients with comorbidities that affect swallowing.1 Liquid oral formulations could be an alternative; however, no commercial oral solution is available for dolutegravir and oral solutions for lamivudine (10 mg/mL, 240 mL/bottle) and abacavir (20 mg/mL, 240 mL/bottle) are not practical to use in adults because of the high volume per dose, and the taste is unpleasant. If HIV-infected patients are critically ill or are unable to swallow tablets for other reasons, antiretroviral medication is often crushed and suspended to ease administration. Depending on the biopharmaceutical characteristics of a drug and its formulation, crushing tablets can influence drug pharmacokinetics (PK). It may shorten the time to reach maximum plasma concentration, as the gastric disintegration phase does not occur, or change bioavailability and the maximum plasma concentration (Cmax). This has been shown for tenofovir, efavirenz and lopinavir, for example.2–4 In addition, a PK interaction between dolutegravir and enteral nutrition is likely to occur on the level of absorption. This assumption is based on the known interaction between dolutegravir and cations in antacids, multivitamins and dietary supplements. Simultaneous oral ingestion of antacids, multivitamins, calcium or iron supplements and dolutegravir was shown to decrease Cmax and AUC of dolutegravir by 33%–74%.5,6 Data on crushing elvitegravir fixed-dose combination tablets could not demonstrate an interaction between elvitegravir and enteral nutrition.7 It is still unclear whether certain foods or liquids containing high amounts of magnesium or other cations, such as enteral nutrition, can cause a decrease in exposure if combined with other integrase inhibitors such as dolutegravir. As altered drug exposure may possibly lead to treatment failure, development of resistance or toxicity, therapeutic drug monitoring is currently recommended or the crushing of TRI is advised against due to a lack of data on PK. Therefore, the aim of this study was to investigate whether crushed and suspended TRI and crushed and suspended TRI with enteral nutrition are bioequivalent to taking TRI as a whole tablet. Patients and methods This open-label, three-period, randomized, single-dose, crossover trial in healthy adult volunteers was conducted in April 2016 at Radboud university medical center, Nijmegen, the Netherlands. Ethics The protocol was approved by the local Ethics Committee of Arnhem-Nijmegen (reference number 2015-2003) and has been registered at ClinicalTrials.gov (NCT02569346). All subjects provided written informed consent prior to study assessments. Patients Healthy volunteers that were eligible for inclusion had to be between 18 and 55 years of age, had to weigh at least 40 kg with a BMI of 18.5–30 kg/m2, had to be able and willing to sign the Informed Consent Form prior to screening evaluations, had to be in good age-appropriate health condition and not have smoked more than 10 cigarettes per day for at least 3 months prior to day 1. Main exclusion criteria were: positive test for HIV, hepatitis B or hepatitis C; positive HLA-B*5701 status; sensitivity/idiosyncrasy to medicinal products or excipients; relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion; pregnant female; therapy with any drug except for acetaminophen; abuse of drugs, alcohol or solvents; gluten-free diet; participation in a drug study; recent donation of blood; and febrile illness. Methods The study was designed to demonstrate bioequivalence between whole-tablet TRI with 200 mL of water (reference treatment) and a crushed and suspended TRI tablet with 200 mL of water (intervention I) and a crushed and suspended TRI tablet with 200 mL of water combined with oral intake of 250 mL (1 kcal/mL) of Nutrison enteral nutrition (Nutricia, Zoetermeer, the Netherlands) (intervention II). Two hundred and fifty millilitres of Nutrison contains 9.75 g of fat, 4 mg of iron, 3 mg of zinc, 200 mg of calcium and 57.5 mg of magnesium. Tablets were crushed with a tablet crusher; ‘narrow’ type (Hammarplast Medical AB, Lidköping, Sweden). Subjects randomly received a single dose of the reference or intervention treatments, with a washout period of 7 days. Power calculation was performed by using a mixed linear model with period and treatment as fixed factors. A total sample size of 18 evaluable subjects was considered sufficient for a power of 80% in the case of bioequivalence. Twenty-two subjects were included to account for possible dropouts. PK curves were collected on day 1, 8 and 15 at the following timepoints: t = 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36 and 48 h after ingestion. Dolutegravir, abacavir and lamivudine plasma concentrations were analysed using an internally and externally validated ultra-performance LC MS method (LC-MS/MS).8 The lower limit of quantification (LLOQ) for dolutegravir, abacavir and lamivudine was 0.01 mg/L, 0.0149 mg/L and 0.0150 mg/L, respectively. PK parameters were determined using a non-compartmental analysis in WinNonlin (version 6.3, Pharsight Corporation, St Louis, USA). Geometric mean ratios (GMRs) with 90% CI of AUC0-∞ and Cmax were calculated for interventions I and II versus the reference treatment after log transformation of within-subject ratios using a fixed-effects bioequivalence module in WinNonlin/Phoenix. Two treatments were considered bioequivalent if the 90% CI of the GMR of AUC0-∞ and Cmax fell within 80%–125%.9 Furthermore, safety and tolerability of a single-dose crushed and suspended TRI tablet with or without enteral nutrition was evaluated. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results Twenty-two healthy adult volunteers (55% male, 91% white and 9% of mixed race) were enrolled in this study, all of whom completed the study. The median (range) age was 25 (18–54) years and median (range) BMI was 23 (20–27) kg/m2. Figure 1 shows the mean plasma concentration versus time profiles of all compounds for each treatment. Table 1 shows the PK parameters for dolutegravir, abacavir and lamivudine of the reference treatment, intervention I and intervention II, and GMRs of both interventions versus the reference treatment. Dolutegravir plasma concentrations for intervention I (crushed and suspended TRI tablet with fasting) were 26% higher compared with the reference treatment (whole-tablet TRI with fasting). Dolutegravir Cmax increased by 30% compared with the reference treatment. Bioequivalence between intervention I and the reference treatment could not be demonstrated as the GMR with 90% CI for AUC0-∞ and Cmax of dolutegravir fell outside the required limits of 80%–125%. For abacavir and lamivudine, all 90% CIs fell within the bioequivalence limits of 80%–125%. Table 1. PK parameters for dolutegravir, abacavir and lamivudine, including GMRs for the interventions versus the reference treatment PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) AUC0-∞, Cmax and t½ are shown as geometric mean (% coefficient of variation). Tmax is shown as median (range). Table 1. PK parameters for dolutegravir, abacavir and lamivudine, including GMRs for the interventions versus the reference treatment PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) AUC0-∞, Cmax and t½ are shown as geometric mean (% coefficient of variation). Tmax is shown as median (range). Figure 1. View largeDownload slide Mean plasma concentration (SD) versus time curves for dolutegravir (a), abacavir (b) and lamivudine (c). Figure 1. View largeDownload slide Mean plasma concentration (SD) versus time curves for dolutegravir (a), abacavir (b) and lamivudine (c). After intake of a crushed and suspended TRI tablet with enteral nutrition (intervention II), dolutegravir plasma concentrations increased by 18% compared with the reference treatment. Dolutegravir Cmax was 22% higher and abacavir Cmax was 17% lower compared with the reference treatment. The 90% CIs of the GMRs for Cmax of both dolutegravir and abacavir, comparing a crushed and suspended TRI tablet with enteral nutrition with whole-tablet TRI, fell outside the predefined bioequivalence range. All other 90% CIs fell within the required limits of 80%–125%. No serious adverse events were reported during the trial. In 77% of the healthy adult volunteers one or more adverse event was observed and reported. Of the reported adverse events, 25/53 (47%) were judged to be probably or possibly related to TRI and the most frequently reported were headache (24%, grade 1–2), nausea (16%, grade 1), fatigue (16%, grade 1) and dizziness, abdominal pain and diarrhoea (all 12%, grade 1). There was one case of difficulty in falling asleep and one case of elevated amylase (both grade 1). All related adverse events were resolved or resolving at the end of the study. Discussion This study shows that crushing and suspending TRI leads to higher dolutegravir exposure (AUC) and Cmax. Bioequivalence could not be demonstrated for a crushed and suspended TRI tablet, either under fasting conditions or combined with enteral nutrition, compared with whole-tablet TRI. One case report was published on an antiretroviral-naive patient who crushed tenofovir disoproxil fumarate/emtricitabine and dolutegravir tablets on his own initiative and mixed them with apple sauce. This patient achieved virological suppression after 4 weeks of treatment with good tolerability. This case report suggests effectiveness of crushed and suspended dolutegravir.10 Our data show higher dolutegravir levels reached after crushing, which supports the sustained effectiveness seen in this case report. As the t½ for dolutegravir was similar in all treatments, the increased dolutegravir exposure is probably caused by enhanced absorption. In our opinion, the increased dolutegravir exposure we observed in this study is not clinically relevant in terms of safety, because dolutegravir exposure is even higher if taken with food11,12 or in twice-daily dosing, which is recommended in patients with HIV-1 with resistance to other integrase inhibitors.13 Besides the effect of crushing and the known effect of food, an interaction between dolutegravir and cations in enteral nutrition is likely to occur. Simultaneous intake with antacids and cation-containing supplements is advised against due to decreased exposure and Cmax of dolutegravir; however, this effect is attenuated when taken with food.6 This study, though, shows that fasting intake of crushed TRI with oral intake of enteral nutrition, which is considered a high-fat liquid, increases dolutegravir exposure. This is in line with results for crushed elvitegravir fixed-dose combination tablets (Stribild®) taken with enteral nutrition.7 Therefore, we assume that the effect of crushing and intake with enteral nutrition sufficiently counteracts the possible negative effect on dolutegravir absorption by cations. Furthermore, decreased abacavir Cmax after crushing and suspending TRI combined with enteral nutrition is similar to results from other studies of abacavir taken with food and considered not clinically relevant.11,14,15 Lamivudine exposure and Cmax were bioequivalent to intake of the whole tablet. As a result, it can be concluded that TRI can be crushed and combined with enteral nutrition without separating intake in time. The combination of a twice-daily dolutegravir dose, intake with food and crushing of dolutegravir altogether, could lead to high plasma concentrations, assuming the maximum absorption has not yet been reached. As data on the relationship between dolutegravir plasma concentrations and toxicity have not yet been fully elucidated, additional monitoring for side effects should be implemented in this situation. This study did not investigate the effects of feeding tubes; therefore, it is unknown whether absorption would be similar in HIV-seropositive patients with different enteral feeding tubes, e.g. different diameter, different characteristics of the tubing material and other tube exit locations in the gastrointestinal tract. Particular care should be taken with tubes exiting beyond the pylorus. A case report described lower-than-expected dolutegravir concentrations in a patient with dolutegravir (50 mg twice daily) administered via an orogastric tube, when compared with patients administered a 100 mg total daily dose. HIV-1 RNA remained undetectable, but the authors would recommend consideration of dolutegravir dose titration (150–200 mg total daily dose) to achieve optimal dolutegravir trough concentrations via the enteral route, especially in the integrase-experienced patient.16 In conclusion, bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition. Acknowledgements Presented at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017 (Poster 429). We wish to thank the healthy volunteers that participated in the trial, the staff of the Clinical Research Centre Nijmegen for conducting the trial and the laboratory technicians of the Department of Pharmacy for the analysis of the PK samples (both at Radboud university medical center, Nijmegen, the Netherlands). Funding Medication was donated for this trial by ViiV Healthcare. Transparency declarations None to declare. References 1 Bossacoma Busquets F , Noguera-Julian A , Sanchez E et al. Dolutegravir plus abacavir/lamivudine works in adolescents, but size matters . J Antimicrob Chemother 2017 ; 72 : 2958 – 60 . Google Scholar CrossRef Search ADS PubMed 2 Best BM , Capparelli EV , Diep H et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children . J Acquir Immune Defic Syndr 2011 ; 58 : 385 – 91 . Google Scholar CrossRef Search ADS PubMed 3 Bastiaans DE , Forcat S , Lyall H et al. Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands . Pediatr Infect Dis J 2014 ; 33 : 301 – 5 . Google Scholar CrossRef Search ADS PubMed 4 King J , McCall M , Cannella A et al. A randomized crossover study to determine relative bioequivalence of tenofovir, emtricitabine, and efavirenz (Atripla) fixed-dose combination tablet compared with a compounded oral liquid formulation derived from the tablet . J Acquir Immune Defic Syndr 2011 ; 56 : e131 – 2 . Google Scholar CrossRef Search ADS 5 Patel P , Song I , Borland J et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers . J Antimicrob Chemother 2011 ; 66 : 1567 – 72 . Google Scholar CrossRef Search ADS PubMed 6 Song I , Borland J , Arya N et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects . J Clin Pharmacol 2015 ; 55 : 490 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Jongbloed-de Hoon M , Colbers A , Velthoven-Graafland K et al. Brief report: pharmacokinetics of crushed elvitegravir combination tablet given with or without enteral nutrition . J Acquir Immune Defic Syndr 2017 ; 74 : 571 – 4 . Google Scholar CrossRef Search ADS PubMed 8 Burger D , Teulen M , Eerland J et al. The international interlaboratory quality control program for measurement of antiretroviral drugs in plasma: a global proficiency testing program . Ther Drug Monit 2011 ; 33 : 239 – 43 . Google Scholar PubMed 9 EMA . Guideline on the Investigation of Bioequivalence. 2010 . http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. 10 Buscemi L. Virological suppression after use of crushed tenofovir-emtricitabine and dolutegravir tablets in a patient with HIV infection . Am J Health Syst Pharm 2016 ; 73 : 1125 – 6 . Google Scholar CrossRef Search ADS PubMed 11 Weller S , Chen S , Borland J et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food . J Acquir Immune Defic Syndr 2014 ; 66 : 393 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Song I , Borland J , Chen S et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir . Antimicrob Agents Chemother 2012 ; 56 : 1627 – 9 . Google Scholar CrossRef Search ADS PubMed 13 EMA . Tivicay; Summary of Product Characteristics. 2014 , last updated 09/10/2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002753/WC500160680.pdf. 14 Yuen GJ , Lou Y , Thompson NF et al. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption . J Clin Pharmacol 2001 ; 41 : 277 – 88 . Google Scholar CrossRef Search ADS PubMed 15 Chittick GE , Gillotin C , McDowell JA et al. Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food . Pharmacotherapy 1999 ; 19 : 932 – 42 . Google Scholar CrossRef Search ADS PubMed 16 Turley SL , Fulco PP. Enteral administration of twice-daily dolutegravir and rilpivirine as a part of a triple-therapy regimen in a critically ill patient with HIV . J Int Assoc Provid AIDS Care 2017 ; 16 : 117 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 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Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure

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Abstract

Abstract Background If HIV patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is crushed and dissolved prior to administration. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq®, referred to as TRI); therefore, crushing of TRI is not recommended. Objectives To investigate whether the TRI fixed-dose combination tablet can be crushed and combined with enteral nutrition without influencing pharmacokinetics (PK). Methods We carried out an open-label, three-period, randomized, single-dose, crossover trial in 22 healthy adult volunteers. Subjects randomly received whole-tablet TRI with fasting (reference), crushed and suspended TRI with fasting or crushed and suspended TRI with oral intake of enteral nutrition. Bioequivalence criteria (80%–125% acceptance range) of AUC0-∞ and Cmax were used. ClinicalTrials.gov: NCT02569346. Results Crushing TRI leads to higher dolutegravir exposure (AUC0-∞: +26% and Cmax: +30%) and, if crushed TRI is combined with enteral nutrition, to a decrease in abacavir Cmax (−17%). Lamivudine concentrations were not affected as geometric mean ratios with 90% CIs fell within the 80%–125% range. Conclusions Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition. Introduction The HIV-1 integrase inhibitor dolutegravir is marketed as a single tablet (Tivicay®) and in a fixed-dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as TRI). TRI is the largest currently available once-daily fixed-dose combination tablet, possibly causing adherence issues in young adolescents and in patients with comorbidities that affect swallowing.1 Liquid oral formulations could be an alternative; however, no commercial oral solution is available for dolutegravir and oral solutions for lamivudine (10 mg/mL, 240 mL/bottle) and abacavir (20 mg/mL, 240 mL/bottle) are not practical to use in adults because of the high volume per dose, and the taste is unpleasant. If HIV-infected patients are critically ill or are unable to swallow tablets for other reasons, antiretroviral medication is often crushed and suspended to ease administration. Depending on the biopharmaceutical characteristics of a drug and its formulation, crushing tablets can influence drug pharmacokinetics (PK). It may shorten the time to reach maximum plasma concentration, as the gastric disintegration phase does not occur, or change bioavailability and the maximum plasma concentration (Cmax). This has been shown for tenofovir, efavirenz and lopinavir, for example.2–4 In addition, a PK interaction between dolutegravir and enteral nutrition is likely to occur on the level of absorption. This assumption is based on the known interaction between dolutegravir and cations in antacids, multivitamins and dietary supplements. Simultaneous oral ingestion of antacids, multivitamins, calcium or iron supplements and dolutegravir was shown to decrease Cmax and AUC of dolutegravir by 33%–74%.5,6 Data on crushing elvitegravir fixed-dose combination tablets could not demonstrate an interaction between elvitegravir and enteral nutrition.7 It is still unclear whether certain foods or liquids containing high amounts of magnesium or other cations, such as enteral nutrition, can cause a decrease in exposure if combined with other integrase inhibitors such as dolutegravir. As altered drug exposure may possibly lead to treatment failure, development of resistance or toxicity, therapeutic drug monitoring is currently recommended or the crushing of TRI is advised against due to a lack of data on PK. Therefore, the aim of this study was to investigate whether crushed and suspended TRI and crushed and suspended TRI with enteral nutrition are bioequivalent to taking TRI as a whole tablet. Patients and methods This open-label, three-period, randomized, single-dose, crossover trial in healthy adult volunteers was conducted in April 2016 at Radboud university medical center, Nijmegen, the Netherlands. Ethics The protocol was approved by the local Ethics Committee of Arnhem-Nijmegen (reference number 2015-2003) and has been registered at ClinicalTrials.gov (NCT02569346). All subjects provided written informed consent prior to study assessments. Patients Healthy volunteers that were eligible for inclusion had to be between 18 and 55 years of age, had to weigh at least 40 kg with a BMI of 18.5–30 kg/m2, had to be able and willing to sign the Informed Consent Form prior to screening evaluations, had to be in good age-appropriate health condition and not have smoked more than 10 cigarettes per day for at least 3 months prior to day 1. Main exclusion criteria were: positive test for HIV, hepatitis B or hepatitis C; positive HLA-B*5701 status; sensitivity/idiosyncrasy to medicinal products or excipients; relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion; pregnant female; therapy with any drug except for acetaminophen; abuse of drugs, alcohol or solvents; gluten-free diet; participation in a drug study; recent donation of blood; and febrile illness. Methods The study was designed to demonstrate bioequivalence between whole-tablet TRI with 200 mL of water (reference treatment) and a crushed and suspended TRI tablet with 200 mL of water (intervention I) and a crushed and suspended TRI tablet with 200 mL of water combined with oral intake of 250 mL (1 kcal/mL) of Nutrison enteral nutrition (Nutricia, Zoetermeer, the Netherlands) (intervention II). Two hundred and fifty millilitres of Nutrison contains 9.75 g of fat, 4 mg of iron, 3 mg of zinc, 200 mg of calcium and 57.5 mg of magnesium. Tablets were crushed with a tablet crusher; ‘narrow’ type (Hammarplast Medical AB, Lidköping, Sweden). Subjects randomly received a single dose of the reference or intervention treatments, with a washout period of 7 days. Power calculation was performed by using a mixed linear model with period and treatment as fixed factors. A total sample size of 18 evaluable subjects was considered sufficient for a power of 80% in the case of bioequivalence. Twenty-two subjects were included to account for possible dropouts. PK curves were collected on day 1, 8 and 15 at the following timepoints: t = 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36 and 48 h after ingestion. Dolutegravir, abacavir and lamivudine plasma concentrations were analysed using an internally and externally validated ultra-performance LC MS method (LC-MS/MS).8 The lower limit of quantification (LLOQ) for dolutegravir, abacavir and lamivudine was 0.01 mg/L, 0.0149 mg/L and 0.0150 mg/L, respectively. PK parameters were determined using a non-compartmental analysis in WinNonlin (version 6.3, Pharsight Corporation, St Louis, USA). Geometric mean ratios (GMRs) with 90% CI of AUC0-∞ and Cmax were calculated for interventions I and II versus the reference treatment after log transformation of within-subject ratios using a fixed-effects bioequivalence module in WinNonlin/Phoenix. Two treatments were considered bioequivalent if the 90% CI of the GMR of AUC0-∞ and Cmax fell within 80%–125%.9 Furthermore, safety and tolerability of a single-dose crushed and suspended TRI tablet with or without enteral nutrition was evaluated. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results Twenty-two healthy adult volunteers (55% male, 91% white and 9% of mixed race) were enrolled in this study, all of whom completed the study. The median (range) age was 25 (18–54) years and median (range) BMI was 23 (20–27) kg/m2. Figure 1 shows the mean plasma concentration versus time profiles of all compounds for each treatment. Table 1 shows the PK parameters for dolutegravir, abacavir and lamivudine of the reference treatment, intervention I and intervention II, and GMRs of both interventions versus the reference treatment. Dolutegravir plasma concentrations for intervention I (crushed and suspended TRI tablet with fasting) were 26% higher compared with the reference treatment (whole-tablet TRI with fasting). Dolutegravir Cmax increased by 30% compared with the reference treatment. Bioequivalence between intervention I and the reference treatment could not be demonstrated as the GMR with 90% CI for AUC0-∞ and Cmax of dolutegravir fell outside the required limits of 80%–125%. For abacavir and lamivudine, all 90% CIs fell within the bioequivalence limits of 80%–125%. Table 1. PK parameters for dolutegravir, abacavir and lamivudine, including GMRs for the interventions versus the reference treatment PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) AUC0-∞, Cmax and t½ are shown as geometric mean (% coefficient of variation). Tmax is shown as median (range). Table 1. PK parameters for dolutegravir, abacavir and lamivudine, including GMRs for the interventions versus the reference treatment PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) PK parameter Reference treatment (whole tablet, fasting) Intervention I (crushed tablet, fasting) Intervention II (crushed tablet, enteral nutrition) Intervention I versus reference treatment, GMR (90% CI) Intervention II versus reference treatment, GMR (90% CI) Dolutegravir AUC0-∞ (mg·h/L) 69.50 (22) 87.49 (15) 82.38 (15) 125.8 (119–133) 118.4 (112–125) Cmax (mg/L) 3.81 (24) 4.94 (18) 4.65 (15) 129.5 (123–136) 121.7 (115–128) Tmax (h) 2.27 (1.00–4.02) 2.00 (0.50–3.00) 2.50 (1.50–4.02) t½ (h) 13.65 (13) 13.63 (20) 13.24 (14) Abacavir AUC0-∞ (mg·h/L) 14.40 (30) 14.31 (30) 13.55 (25) 99.4 (95–104) 94.1 (90–98) Cmax (mg/L) 4.88 (30) 4.95 (31) 4.06 (22) 101.3 (93–110) 83.0 (76–90) Tmax (h) 1.00 (0.50–2.50) 1.00 (0.50–2.00) 1.58 (0.50–2.50) t½ (h) 3.87 (21) 4.33 (26) 4.05 (22) Lamivudine AUC0-∞ (mg·h/L) 14.20 (26) 14.23 (21) 14.30 (21) 100.2 (96–105) 100.6 (96–105) Cmax (mg/L) 2.31 (31) 2.28 (23) 2.47 (21) 98.6 (93–105) 106.7 (100–113) Tmax (h) 2.00 (1.00–3.00) 1.50 (1.00–4.00) 2.00 (1.50–3.00) t½ (h) 13.88 (35) 13.15 (32) 12.27 (27) AUC0-∞, Cmax and t½ are shown as geometric mean (% coefficient of variation). Tmax is shown as median (range). Figure 1. View largeDownload slide Mean plasma concentration (SD) versus time curves for dolutegravir (a), abacavir (b) and lamivudine (c). Figure 1. View largeDownload slide Mean plasma concentration (SD) versus time curves for dolutegravir (a), abacavir (b) and lamivudine (c). After intake of a crushed and suspended TRI tablet with enteral nutrition (intervention II), dolutegravir plasma concentrations increased by 18% compared with the reference treatment. Dolutegravir Cmax was 22% higher and abacavir Cmax was 17% lower compared with the reference treatment. The 90% CIs of the GMRs for Cmax of both dolutegravir and abacavir, comparing a crushed and suspended TRI tablet with enteral nutrition with whole-tablet TRI, fell outside the predefined bioequivalence range. All other 90% CIs fell within the required limits of 80%–125%. No serious adverse events were reported during the trial. In 77% of the healthy adult volunteers one or more adverse event was observed and reported. Of the reported adverse events, 25/53 (47%) were judged to be probably or possibly related to TRI and the most frequently reported were headache (24%, grade 1–2), nausea (16%, grade 1), fatigue (16%, grade 1) and dizziness, abdominal pain and diarrhoea (all 12%, grade 1). There was one case of difficulty in falling asleep and one case of elevated amylase (both grade 1). All related adverse events were resolved or resolving at the end of the study. Discussion This study shows that crushing and suspending TRI leads to higher dolutegravir exposure (AUC) and Cmax. Bioequivalence could not be demonstrated for a crushed and suspended TRI tablet, either under fasting conditions or combined with enteral nutrition, compared with whole-tablet TRI. One case report was published on an antiretroviral-naive patient who crushed tenofovir disoproxil fumarate/emtricitabine and dolutegravir tablets on his own initiative and mixed them with apple sauce. This patient achieved virological suppression after 4 weeks of treatment with good tolerability. This case report suggests effectiveness of crushed and suspended dolutegravir.10 Our data show higher dolutegravir levels reached after crushing, which supports the sustained effectiveness seen in this case report. As the t½ for dolutegravir was similar in all treatments, the increased dolutegravir exposure is probably caused by enhanced absorption. In our opinion, the increased dolutegravir exposure we observed in this study is not clinically relevant in terms of safety, because dolutegravir exposure is even higher if taken with food11,12 or in twice-daily dosing, which is recommended in patients with HIV-1 with resistance to other integrase inhibitors.13 Besides the effect of crushing and the known effect of food, an interaction between dolutegravir and cations in enteral nutrition is likely to occur. Simultaneous intake with antacids and cation-containing supplements is advised against due to decreased exposure and Cmax of dolutegravir; however, this effect is attenuated when taken with food.6 This study, though, shows that fasting intake of crushed TRI with oral intake of enteral nutrition, which is considered a high-fat liquid, increases dolutegravir exposure. This is in line with results for crushed elvitegravir fixed-dose combination tablets (Stribild®) taken with enteral nutrition.7 Therefore, we assume that the effect of crushing and intake with enteral nutrition sufficiently counteracts the possible negative effect on dolutegravir absorption by cations. Furthermore, decreased abacavir Cmax after crushing and suspending TRI combined with enteral nutrition is similar to results from other studies of abacavir taken with food and considered not clinically relevant.11,14,15 Lamivudine exposure and Cmax were bioequivalent to intake of the whole tablet. As a result, it can be concluded that TRI can be crushed and combined with enteral nutrition without separating intake in time. The combination of a twice-daily dolutegravir dose, intake with food and crushing of dolutegravir altogether, could lead to high plasma concentrations, assuming the maximum absorption has not yet been reached. As data on the relationship between dolutegravir plasma concentrations and toxicity have not yet been fully elucidated, additional monitoring for side effects should be implemented in this situation. This study did not investigate the effects of feeding tubes; therefore, it is unknown whether absorption would be similar in HIV-seropositive patients with different enteral feeding tubes, e.g. different diameter, different characteristics of the tubing material and other tube exit locations in the gastrointestinal tract. Particular care should be taken with tubes exiting beyond the pylorus. A case report described lower-than-expected dolutegravir concentrations in a patient with dolutegravir (50 mg twice daily) administered via an orogastric tube, when compared with patients administered a 100 mg total daily dose. HIV-1 RNA remained undetectable, but the authors would recommend consideration of dolutegravir dose titration (150–200 mg total daily dose) to achieve optimal dolutegravir trough concentrations via the enteral route, especially in the integrase-experienced patient.16 In conclusion, bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition. Acknowledgements Presented at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017 (Poster 429). We wish to thank the healthy volunteers that participated in the trial, the staff of the Clinical Research Centre Nijmegen for conducting the trial and the laboratory technicians of the Department of Pharmacy for the analysis of the PK samples (both at Radboud university medical center, Nijmegen, the Netherlands). Funding Medication was donated for this trial by ViiV Healthcare. Transparency declarations None to declare. References 1 Bossacoma Busquets F , Noguera-Julian A , Sanchez E et al. Dolutegravir plus abacavir/lamivudine works in adolescents, but size matters . J Antimicrob Chemother 2017 ; 72 : 2958 – 60 . Google Scholar CrossRef Search ADS PubMed 2 Best BM , Capparelli EV , Diep H et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children . J Acquir Immune Defic Syndr 2011 ; 58 : 385 – 91 . Google Scholar CrossRef Search ADS PubMed 3 Bastiaans DE , Forcat S , Lyall H et al. Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands . Pediatr Infect Dis J 2014 ; 33 : 301 – 5 . Google Scholar CrossRef Search ADS PubMed 4 King J , McCall M , Cannella A et al. A randomized crossover study to determine relative bioequivalence of tenofovir, emtricitabine, and efavirenz (Atripla) fixed-dose combination tablet compared with a compounded oral liquid formulation derived from the tablet . J Acquir Immune Defic Syndr 2011 ; 56 : e131 – 2 . Google Scholar CrossRef Search ADS 5 Patel P , Song I , Borland J et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers . J Antimicrob Chemother 2011 ; 66 : 1567 – 72 . Google Scholar CrossRef Search ADS PubMed 6 Song I , Borland J , Arya N et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects . J Clin Pharmacol 2015 ; 55 : 490 – 6 . Google Scholar CrossRef Search ADS PubMed 7 Jongbloed-de Hoon M , Colbers A , Velthoven-Graafland K et al. Brief report: pharmacokinetics of crushed elvitegravir combination tablet given with or without enteral nutrition . J Acquir Immune Defic Syndr 2017 ; 74 : 571 – 4 . Google Scholar CrossRef Search ADS PubMed 8 Burger D , Teulen M , Eerland J et al. The international interlaboratory quality control program for measurement of antiretroviral drugs in plasma: a global proficiency testing program . Ther Drug Monit 2011 ; 33 : 239 – 43 . Google Scholar PubMed 9 EMA . Guideline on the Investigation of Bioequivalence. 2010 . http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. 10 Buscemi L. Virological suppression after use of crushed tenofovir-emtricitabine and dolutegravir tablets in a patient with HIV infection . Am J Health Syst Pharm 2016 ; 73 : 1125 – 6 . Google Scholar CrossRef Search ADS PubMed 11 Weller S , Chen S , Borland J et al. Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food . J Acquir Immune Defic Syndr 2014 ; 66 : 393 – 8 . Google Scholar CrossRef Search ADS PubMed 12 Song I , Borland J , Chen S et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir . Antimicrob Agents Chemother 2012 ; 56 : 1627 – 9 . Google Scholar CrossRef Search ADS PubMed 13 EMA . Tivicay; Summary of Product Characteristics. 2014 , last updated 09/10/2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002753/WC500160680.pdf. 14 Yuen GJ , Lou Y , Thompson NF et al. Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption . J Clin Pharmacol 2001 ; 41 : 277 – 88 . Google Scholar CrossRef Search ADS PubMed 15 Chittick GE , Gillotin C , McDowell JA et al. Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food . Pharmacotherapy 1999 ; 19 : 932 – 42 . Google Scholar CrossRef Search ADS PubMed 16 Turley SL , Fulco PP. Enteral administration of twice-daily dolutegravir and rilpivirine as a part of a triple-therapy regimen in a critically ill patient with HIV . J Int Assoc Provid AIDS Care 2017 ; 16 : 117 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 22, 2018

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