Kelong Han

Pharmacokinetics of oseltamivir among pregnant and nonpregnant women

We sought to delineate the pharmacokinetics (PK) of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three nonpregnant reproductive-age females served as the control group. The primary PK endpoint was area under the plasma concentration time curve for oseltamivir carboxylate. Pregnancy did not alter the PK parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration time curve was significantly lower (P = .007) and the apparent clearance significantly higher (P = .006) in pregnant women compared with nonpregnant women. Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary to achieve comparable exposure in pregnant and nonpregnant women.

Rapamycin with Antiretroviral Therapy in AIDS-Associated Kaposi Sarcoma: An AIDS Malignancy Consortium Study

Purpose:The mammalian target of rapamycin is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycins safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)–containing and nonnucleoside reverse transcriptase inhibitor (NNRTI)–containing ART regimens, and assess clinical and biological endpoints including KS response and mammalian target of rapamycin-dependent signaling. Methods:Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5–10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phosphoribosomal S6 protein, and phospho-Akt expression. Interleukin 6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored. Results:Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of 4 subjects whose biopsies were studied at ≥day 50 showed decreased phosphoribosomal S6 protein staining. Conclusions:Rapamycin seems safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations but may be exploited to achieve therapeutic benefit.

Population Pharmacokinetic Evaluation with External Validation and Bayesian Estimator of Voriconazole in Liver Transplant Recipients

AbstractObjectives: The objectives of this study were to evaluate the pharmacokinetics of voriconazole in liver transplant patients, probe covariate effects on voriconazole pharmacokinetics, externally validate the model and explore limited sampling strategies (LSSs) using Bayesian approaches. Methods: Full pharmacokinetic profiles were collected within one oral dosing interval from 13 liver transplant patients. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM software. The final model was internally evaluated using bootstrapping and visual predictive check (VPC), and externally validated by predicting additional samples from different patients that were not used for model building. Maximum a posteriori Bayesian estimators were developed to predict the area under the plasma concentration-time curve (AUC) using the validated final model as the a priori model, actual dosing record and covariate values as the input, and a few concentrations (limited sampling) as feedback information (LSS). Mean prediction error (MPE) and mean absolute prediction error (MAPE) were calculated for external validation and LSS. Results: A one-compartment model with an absorption lag time (tlag) adequately described the data. Population estimates of total clearance after oral administration (CL/F) and volume of distribution after oral administration (Vd/F) were 7.92 L/h and 248 L, respectively. Values of CL/F, Vd/F and tlag decreased with post-operative time and converged to stable levels in about 7 post-operative days. CL/F significantly decreased with increased international normalized ratio. Co-administration of pantoprazole, race and alanine aminotransferase were also significantly associated with pharmacokinetic parameters but ultimately excluded in the final model. VPC showed that most of the data fell within the 90% prediction interval and were symmetrically distributed around the median. Additional 52 samples from 19 patients were collected for external validation. MPE was 0.206 μg/mL (not significantly different from zero) and MAPE was 0.99 μg/mL. Compared with trough levels, LSS using two samples or one sample at a different time provided better MPE, MAPE and correlation (R2) between the observed and LSS-predicted AUC. Conclusions: The population model that was developed showed significant association of voriconazole pharmacokinetics with post-operative time and liver function, and was able to predict an independent external dataset. Our observations suggested a need for intravenous administration of voriconazole in the immediate post-operative period before an oral dose can be administrated. LSS using one sample appeared to be sufficient for reasonable AUC estimation.

Population Pharmacokinetics of Cyclosporine in Transplant Recipients

A number of classical pharmacokinetic studies have been conducted in transplant patients. However, they suffer from some limitations, for example, (1) the study design was limited to intense blood sampling in small groups of patients during a certain posttransplant period, (2) patient factors were evaluated one at a time to identify their association with the pharmacokinetic parameters, and (3) mean pharmacokinetic parameters often cannot be precisely estimated due to large intraindividual variability. Population pharmacokinetics provides a potential means of addressing these limitations and is a powerful tool to evaluate the magnitude and consistency of drug exposure. Population pharmacokinetic studies of cyclosporine focused solely on developing limited sampling strategies and Bayesian estimators to estimate drug exposure, have been summarized before, and are, therefore, not a subject of this review. The major focus of this review is to describe factors (demographic factors, hepatic and gastrointestinal functions, drug–drug interactions, genetic polymorphisms of drug metabolizing enzymes and transporters) that have been identified to contribute to the large portion of observed variability in the pharmacokinetics of cyclosporine in transplant patients. This review summarizes and interprets the conclusions as well as the nonlinear mixed-effects modeling methodologies used in such studies. A highly diversified collection of structural models, variability models, and covariate submodels have been evaluated and validated using internal or external validation methods. This review also highlights areas where additional research is warranted to improve the models since a portion of model variability still remains unexplained.

Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation.

Aim The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. Methods Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5 – 21 years), body weight (BWT; 5.9 – 125 kg), and regimens (5 – 15 mg kg–1 biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady‐state exposure was simulated under BWT‐based, body surface area (BSA)‐based, ideal body weight (IBW)‐based, and tier‐based doses. NONMEM and R were used for analyses. Results Typical estimates of clearance, central volume of distribution (V1), and median half‐life were 9.04 ml h–1, 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (Cmin) and 29% higher peak (Cmax) concentrations. BWT‐adjusted clearance and V1 remained unchanged across ages. Paediatric Cmin was similar to adult Cmin under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier‐based doses. Conclusions BWT‐adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA‐based, IBW‐based, and tier‐based doses offered no substantial advantage over the BWT‐based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women

AIMS Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. METHODS A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. RESULTS The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. CONCLUSION Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.