| 1. |
- Wilkins, Justin J., et al.
(författare)
-
Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
- 2011
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 72:1, s. 51-62
-
Tidskriftsartikel (refereegranskat)abstract
- AIM This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients. METHODS Concentration-time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis. RESULTS A two-compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h(-1), respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg(-1)) may be suboptimal in fast eliminators with low body weight. CONCLUSIONS A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators.
|
|
| 2. |
- Zhang, Chao, et al.
(författare)
-
Model-based approach to dose optimization of lopinavir/ritonavir when co-administered with rifampicin
- 2012
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 73:5, s. 758-767
-
Tidskriftsartikel (refereegranskat)abstract
- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Doubling the dose of lopinavir/ritonavir overcomes the effect of rifampicin on lopinavir concentrations. However, lopinavir concentrations are highly variable and side effects occur commonly. Hence optimized dosing could limit the number of patients exposed to high lopinavir concentrations while maintaining adequate lopinavir concentrations.WHAT THIS STUDY ADDS: We built an integrated population pharmacokinetic model of lopinavir and ritonavir, describing the drug-drug interactions between lopinavir, ritonavir and rifampicin. Based on this model, we have predicted that lower doses of lopinavir/ritonavir can be used in patients weighing less than 50 kg. Also, diurnal variations on lopinavir and ritonavir were investigated for both bioavailability and clearance. Objectives: Rifampicin, a key component of antitubercular treatment, profoundly reduces lopinavir concentrations. The aim of this study was to develop an integrated population pharmacokinetic model accounting for the drug-drug interactions between lopinavir, ritonavir and rifampicin, and to evaluate optimal doses of lopinavir/ritonavir when co-administered with rifampicin.Methods: Steady state pharmacokinetics of lopinavir and ritonavir were sequentially evaluated after the introduction of rifampicin and gradually escalating the dose in a cohort of 21 HIV-infected adults. Intensive pharmacokinetic sampling was performed after each dose adjustment following a morning dose administered after fasting overnight. A population pharmacokinetic analysis was conducted using NONMEM 7.Results: A simultaneous integrated model was built. Rifampicin reduced the oral bioavailability of lopinavir and ritonavir by 20% and 45% respectively, and it increased their clearance by 71% and 36% respectively. With increasing concentrations of ritonavir, clearance of lopinavir decreased in an E(max) relationship. Bioavailability was 42% and 45% higher for evening doses compared to morning doses for lopinavir and ritonavir, respectively, while oral clearance of both drugs was 33% lower overnight. Simulations predicted that 99.5% of our patients receiving doubled doses of lopinavir/ritonavir achieve morning trough concentrations of lopinavir > 1 mg/L during rifampicin co-administration, and 95% of those weighing less than 50 kg achieve this target already with 600/150 mg doses of lopinavir/ritonavir.Conclusions: The model describes the drug-drug interactions between lopinavir, ritonavir and rifampicin in adults. The higher trough concentrations observed in the morning were explained by both higher bioavailability with the evening meal and lower clearance overnight.
|
|
| 3. |
- Zhang, Chao, et al.
(författare)
-
Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin
- 2013
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 76:5, s. 741-751
-
Tidskriftsartikel (refereegranskat)abstract
- AimsRifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults. MethodsAn integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy. ResultsThe bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults. ConclusionsThe model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug-drug interactions should be evaluated in paediatric patient populations.
|
|
