Tuberculosis is the most common cause of death in HIV‐infected patients. Isoniazid is used as a first‐line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co‐infected patients is therefore critical. Plasma levels of isoniazid, acetyl‐isoniazid, and isonicotinic acid from 63 patients co‐infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed‐effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz‐based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3‐fold and 2.3‐fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz‐based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl‐isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid‐related toxicity and treatment failure is presented.

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This study aimed to characterize the population pharmacokinetics and pharmacogenetics of ethambutol in tuberculosis-HIV-coinfected adult patients. Ethambutol plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, in 63 patients receiving ethambutol as part of rifampin-based fixed-dose combination therapy for tuberculosis were analyzed using nonlinear mixed-effects modeling. A one-compartment disposition model with first-order elimination and four transit compartments prior to first-order absorption was found to adequately describe the concentration-time profiles of ethambutol in plasma. Body weight was implemented as an allometric function on the clearance and volume parameters. Estimates of oral clearance and volume of distribution were 77.4 liters/h and 76.2 liters, respectively. A G/A mutation with regard to CYP1A2 2159 G>A was associated with a 50% reduction in relative bioavailability. Simulations revealed that doses of 30 mg/kg of body weight and 50 mg/kg for G/G and G/A carriers, respectively, would result in clinically adequate exposure. The results presented here suggest that CYP1A2 polymorphism affects ethambutol exposure in this population and that current treatment guidelines may result in underexposure in patients coinfected with tuberculosis and HIV. Based on simulations, a dose increase from15 to 20 mg/kg to 30 mg/kg is suggested. However, the 50-mg/kg dose required to reach therapeutic exposure in G/A carriers may be inappropriate due to the dose-dependent toxicity of ethambutol. Additional studies are required to further investigate CYP450 polymorphism effects on ethambutol pharmacokinetics.

Background Artemisinin-based combination therapy is recommended as first-line anti-malarial treatment worldwide. A combination of artemisinin with the long acting drug piperaquine has shown high efficacy and tolerability in patients with uncomplicated Plasmodium falciparum infections. The aim of this study was to characterize the population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers after two different dose sizes, formulations and in a combination with piperaquine. A secondary aim was to compare two different methods for the evaluation of bioequivalence of the formulations.MethodsFifteen subjects received four different dose regimens of a single dose of artemisinin as a conventional formulation (160 and 500 mg) and as a micronized test formulation (160 mg alone and in combination with piperaquine phosphate, 360 mg) with a washout period of 3 weeks between each period (i.e. four-way cross-over). Venous plasma samples were collected frequently up to 12 h after dose in each period. Artemisinin was quantified in plasma using liquid chromatography coupled with tandem mass spectrometry. A nonlinear mixed-effects modelling approach was utilized to evaluate the population pharmacokinetic properties of the drug and to investigate the clinical impact of different formulations.ResultsThe plasma concentration–time profiles for artemisinin were adequately described by a transit-absorption model with a one-compartment disposition, in all four sequences simultaneously. The mean oral clearance, volume of distribution and terminal elimination half-life was 417 L/h, 1210 L and 1.93 h, respectively. Influence of formulation, dose and possible interaction of piperaquine was evaluated as categorical covariates in full covariate approaches. No clinically significant differences between formulations were shown which was in accordance with the previous results using a non-compartmental bioequivalence approach.ConclusionsThis is the first population pharmacokinetic characterization of artemisinin in healthy volunteers. Increasing the dose resulted in a significant increase in the mean transit-time but the micronized formulation or concomitant piperaquine administration did not affect the pharmacokinetic properties of artemisinin. The results from the traditional bioequivalence evaluation were comparable with results obtained from mixed-effects modelling.

For the first time, a bioanalytical method for determination of artesunate and dihydroartemisinin in human saliva has been described, showing possible applicability in clinical saliva samples in addition to plasma samples.