Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid

Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid Sir, Among the large spectrum of neurological disorders that can affect people living with HIV, seizures have been commonly reported.1 Before introducing new anticonvulsants, possible drug–drug interactions (DDIs) with antiretrovirals (ARVs) should be ruled out. DDIs may result in altered concentrations of both classes of drugs, leading to uncontrolled epilepsy, toxicity or emergence of drug-associated resistance mutations and ART failure.2 In HIV-positive patients, valproic acid is often used due to its mood-modulating properties and its favourable pharmacokinetic profile.1 Although concurrent use of valproic acid with older ARVs has been described,3 to date, no study has ruled out potential DDIs between valproic acid and the newest integrase inhibitor, dolutegravir. Both drugs are highly protein-bound4,5 and share secondary metabolizing pathways. Valproic acid is metabolized through glucuronidation by several uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes, through β-oxidation in mitochondria and, to a lesser extent, through cytochrome P450.4 Dolutegravir is mainly metabolized by UGT1A1, but it is also a substrate of UGT1A3, UGT1A9 and CYP3A4.5 To better understand the determinants of dolutegravir plasma concentration in the clinical setting, we performed a registry analysis on data collected from Torino Therapeutic Drug Monitoring (TDM) laboratory.6 Plasma concentrations were measured at steady-state through a validated UPLC-MS/MS method with a limit of detection of 0.0117 μg/mL.7 Three hundred and sixty-three trough samples were withdrawn 21–27 h after drug intake in 149 patients. In seven patients on valproic acid (11 samples) lower dolutegravir trough concentrations were observed (median 0.068 μg/mL, IQR 0.037–0.148 μg/mL, minimum–maximum non-detectable–0.829 μg/mL) versus those not on valproic acid (median 0.557 μg/mL, IQR 0.290–1.135 μg/mL, minimum–maximum non-detectable–6.726 μg/mL). The highest dolutegravir concentration with valproic acid (0.829 μg/mL) was observed in a patient concomitantly receiving atazanavir, which is known to decrease dolutegravir metabolism through UGT1A1 inhibition.8 One patient had several trough levels measured and, despite other concomitant detectable ARVs, dolutegravir plasma concentrations were persistently low (Figure S1, available as Supplementary data at JAC Online).6 Following this preliminary observation, we performed detailed pharmacokinetic evaluations in two hospitalized patients requiring valproic acid while on dolutegravir-based regimens. Both signed written informed consent for sample withdrawal and data publication. The first patient was a woman admitted with progressive multifocal leucoencephalopathy and seizures. While on dolutegravir twice daily, she started valproic acid and lacosamide. Valproic acid was first administered intravenously (500 mg q8h) and then as oral modified-release tablets (500 mg q8h); 3 months later the oral dose was reduced to 250 mg q8h. Dolutegravir and valproic acid were measured at steady-state at five timepoints (pre-dose and 1, 3, 5 and 12 h after dose). Dolutegravir AUC, Cmin and Cmax showed variable profiles (Figure 1), while valproic acid concentrations were in the therapeutic range, between 50 and 100 μg/mL. With intravenous valproic acid, dolutegravir AUC was 82% lower than the mean reference AUC value for dolutegravir q12h (75.1 μg·h/mL),8 with oral valproic acid 500 mg q8h it was 87% lower and with oral valproic acid 250 mg q8h it was 90.5% lower. Figure 1 View largeDownload slide Dolutegravir and valproic acid plasma concentrations in patient 1 (left) and patient 2 (right). Filled circles represent dolutegravir with intravenous valproic acid 1500 mg, filled squares represent dolutegravir with oral valproic acid 1500 mg and filled triangles represent dolutegravir with oral valproic acid 750 mg. DTG, dolutegravir; VPA, valproic acid; iv, intravenous; po, oral. Figure 1 View largeDownload slide Dolutegravir and valproic acid plasma concentrations in patient 1 (left) and patient 2 (right). Filled circles represent dolutegravir with intravenous valproic acid 1500 mg, filled squares represent dolutegravir with oral valproic acid 1500 mg and filled triangles represent dolutegravir with oral valproic acid 750 mg. DTG, dolutegravir; VPA, valproic acid; iv, intravenous; po, oral. The second instance was a female patient with bipolar disorder taking oral valproic acid 500 mg q8h, admitted with primary HIV infection. Intensified ART was started on admission with darunavir/ritonavir 600/100 mg q12h, dolutegravir 50 mg q24h and emtricitabine/tenofovir 200/245 mg q24h. Dolutegravir and valproic acid were measured 10 days after treatment initiation at six timepoints (pre-dose and 1, 3, 5, 12 and 24 h after dose). AUC was 80% lower than the mean reference value for dolutegravir q24h (53.6 μg·h/mL),8 whereas Cmin was reduced by 87% (mean reference value 1.11 μg/mL).8 Although this result could partially be explained by the known interaction between dolutegravir and darunavir,8 the reduction in dolutegravir plasma concentrations was so high that other mechanisms need to be considered. Despite the small number of cases, these data may suggest a possible interaction between valproic acid and dolutegravir; the size of this potential DDI was relevant although both patients had dolutegravir plasma concentrations above the protein-adjusted 90% inhibitory quotient (0.064 μg/mL). Nevertheless this may be important for integrase inhibitor-exposed patients with HIV carrying resistance-associated mutations; the virological outcome of the two patients is unfortunately unavailable (one died and the other one was lost to follow-up). The mechanisms leading to this possible DDI are unknown. Dolutegravir absorption may be limited from excipients contained in some valproic acid gastro-resistant oral formulations, such as magnesium stearate. Magnesium, being a divalent ion, can chelate dolutegravir, reducing its absorption.5 Dolutegravir plasma concentrations were lower with reduced valproic acid doses at later observations: prolonged therapies with valproic acid might favour a progressive enzymatic induction of dolutegravir-metabolizing enzymes (such as CYP3A4 and UGT1A1) or dolutegravir-transporting enzymes (such as P-glycoprotein).9,10 Our small case series highlights a need to monitor a potential DDI between dolutegravir and valproic acid. Formal pharmacokinetic studies are needed in order to identify the magnitude and possible mechanisms of interaction. Meanwhile, we suggest careful clinical monitoring and performance of TDM in patients taking both dolutegravir and valproic acid who may be at a higher risk of failing on dolutegravir-containing regimens. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. Supplementary data Figure S1 appears as Supplementary data at JAC Online. References 1. Kirmani BF, Mungall-Robinson D. Role of anticonvulsants in the management of AIDS related seizures. Front Neurol  2014; 5: 10. Google Scholar PubMed  2. Bonora S, Calcagno A, Fontana S et al.   Clinically significant drug interaction between tipranavir-ritonavir and phenobarbital in an HIV-infected subject. Clin Infect Dis  2007; 45: 1654– 5. Google Scholar CrossRef Search ADS PubMed  3. DiCenzo R, Peterson D, Cruttenden K et al.   Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother  2004; 48: 4328– 31. Google Scholar CrossRef Search ADS PubMed  4. Ghodke-Puranik Y, Thorn CF, Lamba JK et al.   Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics  2013; 23: 236– 41. Google Scholar CrossRef Search ADS PubMed  5. Cottrell ML, Hadzic T, Kashuba A. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet  2013; 52: 981– 94. Google Scholar CrossRef Search ADS PubMed  6. Alcantarini C, Calcagno A, Marinaro L et al.   Determinants of dolutegravir plasma concentrations in the clinical setting. In: Abstracts of the International Congress of Drug Therapy in HIV Infection, Glasgow, UK, 2016. Abstract P304. JIAS  2016; 19 Suppl 7. 7. Simiele M, Ariaudo A, De Nicolo A et al.   UPLC–MS/MS method for the simultaneous quantification of three new antiretroviral drugs, dolutegravir, elvitegravir and rilpivirine, and other thirteen antiretroviral agents plus cobicistat and ritonavir boosters in human plasma. J Pharm Biomed Anal  2017; 138: 223– 30. Google Scholar CrossRef Search ADS PubMed  8. ViiV Healthcare. Tivicay® - Summary of Product Characteristics (SPC). https://www.medicines.org.uk/emc/medicine/28545. 9. Zhang L, Chu X, Wang H et al.   Dysregulations of UDP-glucuronosyltransferases in rats with valproic acid and high fat diet induced fatty liver. Eur J Pharmacol  2013; 721: 277– 85. Google Scholar CrossRef Search ADS PubMed  10. Cerveny L, Svecova L, Anzenbacherova E et al.   Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos  2007; 35: 1032– 41. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

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Oxford University Press
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© The Author 2017. 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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10.1093/jac/dkx461
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Abstract

Sir, Among the large spectrum of neurological disorders that can affect people living with HIV, seizures have been commonly reported.1 Before introducing new anticonvulsants, possible drug–drug interactions (DDIs) with antiretrovirals (ARVs) should be ruled out. DDIs may result in altered concentrations of both classes of drugs, leading to uncontrolled epilepsy, toxicity or emergence of drug-associated resistance mutations and ART failure.2 In HIV-positive patients, valproic acid is often used due to its mood-modulating properties and its favourable pharmacokinetic profile.1 Although concurrent use of valproic acid with older ARVs has been described,3 to date, no study has ruled out potential DDIs between valproic acid and the newest integrase inhibitor, dolutegravir. Both drugs are highly protein-bound4,5 and share secondary metabolizing pathways. Valproic acid is metabolized through glucuronidation by several uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes, through β-oxidation in mitochondria and, to a lesser extent, through cytochrome P450.4 Dolutegravir is mainly metabolized by UGT1A1, but it is also a substrate of UGT1A3, UGT1A9 and CYP3A4.5 To better understand the determinants of dolutegravir plasma concentration in the clinical setting, we performed a registry analysis on data collected from Torino Therapeutic Drug Monitoring (TDM) laboratory.6 Plasma concentrations were measured at steady-state through a validated UPLC-MS/MS method with a limit of detection of 0.0117 μg/mL.7 Three hundred and sixty-three trough samples were withdrawn 21–27 h after drug intake in 149 patients. In seven patients on valproic acid (11 samples) lower dolutegravir trough concentrations were observed (median 0.068 μg/mL, IQR 0.037–0.148 μg/mL, minimum–maximum non-detectable–0.829 μg/mL) versus those not on valproic acid (median 0.557 μg/mL, IQR 0.290–1.135 μg/mL, minimum–maximum non-detectable–6.726 μg/mL). The highest dolutegravir concentration with valproic acid (0.829 μg/mL) was observed in a patient concomitantly receiving atazanavir, which is known to decrease dolutegravir metabolism through UGT1A1 inhibition.8 One patient had several trough levels measured and, despite other concomitant detectable ARVs, dolutegravir plasma concentrations were persistently low (Figure S1, available as Supplementary data at JAC Online).6 Following this preliminary observation, we performed detailed pharmacokinetic evaluations in two hospitalized patients requiring valproic acid while on dolutegravir-based regimens. Both signed written informed consent for sample withdrawal and data publication. The first patient was a woman admitted with progressive multifocal leucoencephalopathy and seizures. While on dolutegravir twice daily, she started valproic acid and lacosamide. Valproic acid was first administered intravenously (500 mg q8h) and then as oral modified-release tablets (500 mg q8h); 3 months later the oral dose was reduced to 250 mg q8h. Dolutegravir and valproic acid were measured at steady-state at five timepoints (pre-dose and 1, 3, 5 and 12 h after dose). Dolutegravir AUC, Cmin and Cmax showed variable profiles (Figure 1), while valproic acid concentrations were in the therapeutic range, between 50 and 100 μg/mL. With intravenous valproic acid, dolutegravir AUC was 82% lower than the mean reference AUC value for dolutegravir q12h (75.1 μg·h/mL),8 with oral valproic acid 500 mg q8h it was 87% lower and with oral valproic acid 250 mg q8h it was 90.5% lower. Figure 1 View largeDownload slide Dolutegravir and valproic acid plasma concentrations in patient 1 (left) and patient 2 (right). Filled circles represent dolutegravir with intravenous valproic acid 1500 mg, filled squares represent dolutegravir with oral valproic acid 1500 mg and filled triangles represent dolutegravir with oral valproic acid 750 mg. DTG, dolutegravir; VPA, valproic acid; iv, intravenous; po, oral. Figure 1 View largeDownload slide Dolutegravir and valproic acid plasma concentrations in patient 1 (left) and patient 2 (right). Filled circles represent dolutegravir with intravenous valproic acid 1500 mg, filled squares represent dolutegravir with oral valproic acid 1500 mg and filled triangles represent dolutegravir with oral valproic acid 750 mg. DTG, dolutegravir; VPA, valproic acid; iv, intravenous; po, oral. The second instance was a female patient with bipolar disorder taking oral valproic acid 500 mg q8h, admitted with primary HIV infection. Intensified ART was started on admission with darunavir/ritonavir 600/100 mg q12h, dolutegravir 50 mg q24h and emtricitabine/tenofovir 200/245 mg q24h. Dolutegravir and valproic acid were measured 10 days after treatment initiation at six timepoints (pre-dose and 1, 3, 5, 12 and 24 h after dose). AUC was 80% lower than the mean reference value for dolutegravir q24h (53.6 μg·h/mL),8 whereas Cmin was reduced by 87% (mean reference value 1.11 μg/mL).8 Although this result could partially be explained by the known interaction between dolutegravir and darunavir,8 the reduction in dolutegravir plasma concentrations was so high that other mechanisms need to be considered. Despite the small number of cases, these data may suggest a possible interaction between valproic acid and dolutegravir; the size of this potential DDI was relevant although both patients had dolutegravir plasma concentrations above the protein-adjusted 90% inhibitory quotient (0.064 μg/mL). Nevertheless this may be important for integrase inhibitor-exposed patients with HIV carrying resistance-associated mutations; the virological outcome of the two patients is unfortunately unavailable (one died and the other one was lost to follow-up). The mechanisms leading to this possible DDI are unknown. Dolutegravir absorption may be limited from excipients contained in some valproic acid gastro-resistant oral formulations, such as magnesium stearate. Magnesium, being a divalent ion, can chelate dolutegravir, reducing its absorption.5 Dolutegravir plasma concentrations were lower with reduced valproic acid doses at later observations: prolonged therapies with valproic acid might favour a progressive enzymatic induction of dolutegravir-metabolizing enzymes (such as CYP3A4 and UGT1A1) or dolutegravir-transporting enzymes (such as P-glycoprotein).9,10 Our small case series highlights a need to monitor a potential DDI between dolutegravir and valproic acid. Formal pharmacokinetic studies are needed in order to identify the magnitude and possible mechanisms of interaction. Meanwhile, we suggest careful clinical monitoring and performance of TDM in patients taking both dolutegravir and valproic acid who may be at a higher risk of failing on dolutegravir-containing regimens. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. Supplementary data Figure S1 appears as Supplementary data at JAC Online. References 1. Kirmani BF, Mungall-Robinson D. Role of anticonvulsants in the management of AIDS related seizures. Front Neurol  2014; 5: 10. Google Scholar PubMed  2. Bonora S, Calcagno A, Fontana S et al.   Clinically significant drug interaction between tipranavir-ritonavir and phenobarbital in an HIV-infected subject. Clin Infect Dis  2007; 45: 1654– 5. Google Scholar CrossRef Search ADS PubMed  3. DiCenzo R, Peterson D, Cruttenden K et al.   Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother  2004; 48: 4328– 31. Google Scholar CrossRef Search ADS PubMed  4. Ghodke-Puranik Y, Thorn CF, Lamba JK et al.   Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics  2013; 23: 236– 41. Google Scholar CrossRef Search ADS PubMed  5. Cottrell ML, Hadzic T, Kashuba A. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet  2013; 52: 981– 94. Google Scholar CrossRef Search ADS PubMed  6. Alcantarini C, Calcagno A, Marinaro L et al.   Determinants of dolutegravir plasma concentrations in the clinical setting. In: Abstracts of the International Congress of Drug Therapy in HIV Infection, Glasgow, UK, 2016. Abstract P304. JIAS  2016; 19 Suppl 7. 7. Simiele M, Ariaudo A, De Nicolo A et al.   UPLC–MS/MS method for the simultaneous quantification of three new antiretroviral drugs, dolutegravir, elvitegravir and rilpivirine, and other thirteen antiretroviral agents plus cobicistat and ritonavir boosters in human plasma. J Pharm Biomed Anal  2017; 138: 223– 30. Google Scholar CrossRef Search ADS PubMed  8. ViiV Healthcare. Tivicay® - Summary of Product Characteristics (SPC). https://www.medicines.org.uk/emc/medicine/28545. 9. Zhang L, Chu X, Wang H et al.   Dysregulations of UDP-glucuronosyltransferases in rats with valproic acid and high fat diet induced fatty liver. Eur J Pharmacol  2013; 721: 277– 85. Google Scholar CrossRef Search ADS PubMed  10. Cerveny L, Svecova L, Anzenbacherova E et al.   Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos  2007; 35: 1032– 41. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. 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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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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