Supervisors info:
Ευάγγελος Καραλής, Επίκουρος Καθηγητής Τμήματος Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Introduction: Hydrochlorothiazide (HCTZ) in one of the most widely prescribed diuretic drugs for the treatment of hypertension and oedema. However, the available information in the literature, regarding the population pharmacokinetic properties of HCTZ, is limited.
Objectives: To apply population pharmacokinetic (PK) modeling for the description of the HCTZ kinetics. In addition, to investigate the potential role of covariates in the explanation of the variability of HCTZ kinetics among subjects.
Methods: Hydrochlorothiazide plasma concentration (C) – time (t) data were taken from a single dose, 2x2 bioequivalence study in 34 volunteers under fasting conditions. Each volunteer received a single oral dose of 12.5 mg HCTZ of either the Test (Losartan & Hydrochlorothiazide / Verisfied) or Reference product (Ηyzaar / Merck Sharp Dohme) (50+12.5). HCTZ data were analyzed using a validated HPLC/MS/MS methodology. Nonlinear mixed effect modeling was applied in order to describe the kinetics of HCTZ. Several structural (one-, two-, and three-compartment) and residual error (additive, proportional, combined) models were evaluated. Also, other possibilities for kinetics were explored like biphasic elimination and delayed absorption using a lag-time (Tlag). The optimization of the results was made through the use of some Monolix features like the application of CENS conditions and the truncation of time points. The effects of ‘period’ and ‘treatment’ were assessed for their impact on HCTZ kinetics. Other potential variables evaluated as potential covariates were body weight, gender, height, age, creatinine clearance, glucose levels, liver enzymes, and several other biochemical laboratory values. Evaluation of the results was based on goodness-of-fit plots, statistical information criteria (-2LL, Akaike and Bayesian information criteria), and the physiological soundness of the derived parameters. The entire computational task was performed in Monolix 2016R1.
Results: A two-compartment model with first-order absorption using a lag-time and elimination from the central compartment was found to describe best the C-t profiles of HCTZ. Elimination was found to follow first-order kinetics and take place in the central compartment. The use of a combined error (i.e. the combination of additive and proportional) model led to the optimum results. The following estimates were found for the pharmacokinetic parameters: Tlag=0.487 h, absorption rate constant (ka) = 0.844 h-1, apparent clearance (CL/F) = 33,300 mL/h, apparent inter-compartmental clearance (Q/F) = 19,000 mL/h, apparent volumes of distribution of the central (Vc/F) and the peripheral (Vp/F) compartment were 148,000 mL and 169,000 mL, respectively. Age and body weight were found to contribute significantly to clearance and inter-compartmental clearance, respectively. It has been observed that as age increases, HCTZ clearance declines, whereas the increase of body weight leads to a rise of Q. Finally, the ‘treatment’ and ‘period’ effect were not significant (p>0.05). This finding further ensures the similarity between the two tested drug products (Test vs. Reference).
Conclusions: A population pharmacokinetic model was developed for the description of HCTZ kinetics. Age and body weight were found to be important for determination of the pharmacokinetics of HCTZ. Additional research in this field, by enrolling subjects with impaired renal function or increased body weight, could further improve our knowledge regarding the HCTZ pharmacokinetics and its safe/efficacious use.
Keywords:
population pharmacokinetics, hydrochlorothiazide, nonlinear mixed effect modeling, covariates
