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Abstract: Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3‐period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ. Whole‐blood samples collected between 0 and 24 hours on protein saver cards across the study periods were processed and analyzed for AQ and PGZ contents. Pharmacokinetic parameters were derived by a noncompartmental analysis. Geometric mean ratios for the Cmax, area under the concentration‐time curve for 24 hours (AUC0‐24h), and AUC0‐∞, alongside their corresponding 90%CIs, were compared across the study periods to infer clinically significant changes in disposition. The coadministration of AQ and PGZ resulted in decreases of about 38% and 54% in the Cmax and AUC0‐24h of AQ, respectively. For PGZ, the Cmax increased by about 50%, and AUC0‐24 rose by 48%. The 90%CIs of geometric mean ratios for the Cmax, AUC0‐24h, and AUC0‐∞ were all outside the expected bioequivalence interval of 80% to 125% for both drugs, implying significant interactions. These findings suggest that a bidirectional interaction between AQ and PGZ, with likely implications for the therapy and toxicity of both drugs, may occur in the event of their coadministration. [ABSTRACT FROM AUTHOR]

Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population. A total of 250 plasma concentrations from 126 chronic myeloid leukemia patients were quantified using a validated method. A population pharmacokinetic model was fitted to the data using NONMEM VII software, and the influences of 12 covariates were investigated. The mean population-derived apparent steady-state clearance, elimination half-life, area under the concentration-time curve over 24 hours, and volume of distribution were 17.2 ± 1.8 L/h., 12.05 ± 2.1 hours, 23.26 ± 0.6 μg·h/mL, and 299 ± 20.4 L, respectively. Whole blood count, ethnicity, CYP3A5*3, and ABCB1 C3435T were found to have significant influence on the apparent clearance, while the interindividual variability in clearance and interoccasion variability in bioavailability were 17.4% and 20.4%, respectively. There was a wide variability in apparent clearance and area under the curve compared to those reported in other populations. Thus, treatment with a standard dose of imatinib in this population may not produce the desired effect in most of the patients, whereas continuous exposure to a low drug concentration could lead to pharmacokinetic-derived resistance. The authors suggest the need for therapeutic drug monitoring-guided dose individualization in this population. [ABSTRACT FROM AUTHOR]