POSSIBLE WAYS OF STUDYING PHARMACOKINETIC
PARAMETERS OF CALCIUM PREPARATIONS
N. N. Eremenko,
E. V. Shikh,
S. Yu. Serebrova,
and D. V. Goryachev
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 3, pp.7–9,March, 2018.
Original article submitted February 2, 2018.
Issues pertaining to determination of the pharmacokinetic parameters of calcium preparations are examined
using their comparative bioavailability as an example. Pharmacokinetic parameters of calcium such as area
under the concentration—time curve (AUC) and maximum concentration (C
) are calculated considering
the background calcium contents in volunteers. Calcium excretion with urine is assessed as clearance of
creatinine, a calcium elimination factor. The dynamics of the content of parathormone (PTH), the main hor-
mone regulating calcium homeostasis, are studied. The results can be used to plan clinical trials for assessing
the pharmacokinetics of drug analogs of endogenous compounds.
Keywords: comparative pharmacokinetics, clinical trials in vivo, endogenous compounds, calcium, cal-
cium-creatinine coefficient, parathormone.
Calcium (Ca) salts currently serve as the basis for a large
number of drugs registered in the RF according to the official
portal of the State Drug Registry (SDR) . Calcium prepa-
rations are interesting because they are needed to correct var-
ious Ca metabolic disorders [2 – 6]. Comparative pharmaco-
kinetic studies of the in vivo bioavailability and bioequiva-
lence may be performed to register new drugs based on Ca
salts [7 – 10]. According to the EMA and EAEU [8, 10],
equivalence is preferably assessed using pharmacokinetic in-
stead of clinical studies because the latter are less sensitive
and can require the inclusion of a significant number of sub-
jects to achieve sufficient statistical significance [8, 10].
Several factors must be considered in planning such
First, preparations based on Ca salts are analogs of en-
dogenous compounds. The area under the concentra-
tion—time curve (AUC) of an endogenous substance com-
prises the sum of its background and exogenous concentra-
tions [11 – 14]. Thus, measured pharmacokinetic parameters
must be corrected for its background content.
Second, the blood-plasma Ca concentration stabilizes af-
ter drug administration because homeostasis regulation me-
chanisms are activated in the body. It must be considered that
existing homeostatic mechanisms for maintaining the endog-
enous Ca level within physiological norms do not allow its
concentration to reach a toxic level [11 – 13]. Thus, Ca elim-
ination factors must be compared to assess correctly the se-
rum Ca concentration.
Third, a combination of pharmacokinetic and pharmaco-
dynamic approaches is considered reasonable for a compara-
tive assessment of the pharmacokinetics of endogenous sub-
Endpoints should be clearly defined as control parame-
ters for pharmacodynamic equivalence studies and can be
used as a basis to calculate when a response from the organ-
ism begins to manifest (if this can be measured and is clini-
cally significant) and its intensity . Surrogate endpoints,
which could be Ca homeostasis parameters or biomarkers,
are more rational choices for Ca preparations. According to
EAEU recommendations for choosing a measurable parame-
ter, the measured response should be a pharmacological ef-
fect characterizing the efficacy and (or) safety of the drug
. Intact parathormone (PTH), which is a key hormone in
Ca homeostasis regulation, can act as the measured response.
Reduction of the PTH concentration after administration of a
drug containing Ca is evidence of a biologically significant
Pharmaceutical Chemistry Journal, Vol. 52, No. 3, June, 2018 (Russian Original Vol. 52, No. 3, March, 2018)
0091-150X/18/5203-0195 © 2018 Springer Science+Business Media, LLC
Scientific Center for Expert Evaluation of Medicinal Products, Ministry of
Public Health of the Russian Federation, 8/2 Petrovskii Blvd., Moscow,
127051 Russia; e-mail: Eremenko@expmed.ru
Sechenov First Moscow State Medical University, 8/2 Trubetskaya St.,
Moscow, 119991 Russia.