Rob ter Heine

Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

Purpose: To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer. Experimental Design: A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. Results: The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 ± 1.5 and 2.8 ± 1.4 mg/h/L, respectively, compared with 1.9 ± 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% ± 90% and 161% ± 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated. Conclusion: Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.

Intracellular and plasma steady‐state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre‐treated HIV‐infected patients

AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l(-1) in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance.

Erlotinib and pantoprazole: a relevant interaction or not?

AIMS There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent. METHODS Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole. RESULTS Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally. CONCLUSIONS More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.

Simultaneous quantification of emtricitabine and tenofovir nucleotides in peripheral blood mononuclear cells using weak anion-exchange liquid chromatography coupled with tandem mass spectrometry

Emtricitabine (FTC) and tenofovir (TFV) are widely used antiviral agents that require intracellular phosphorylation to become active. This article describes the development and validation of an assay for the simultaneous quantification of FTC mono-, di- and triphosphate (FTC-MP, -DP and -TP), TFV and TFV mono- and diphosphate (TFV-MP and -DP) in peripheral blood mononuclear cells. Reference compounds and internal standards were obtained by thermal degradation of FTC-TP, TFV-DP, stable isotope-labeled TFV-DP and stable isotope-labeled cytosine triphosphate. Cells were lysed in methanol:water (70:30, v/v) and the extracted nucleotides were analyzed using weak anion-exchange chromatography coupled with tandem mass spectrometry. Calibration ranges in PBMC lysate from 0.727 to 36.4, 1.33 to 66.4 and 1.29 to 64.6 nM for FTC-MP, FTC-DP and FTC-TP and from 1.51 to 75.6, 1.54 to 77.2 and 2.54 to 127 nM for TFV, TFV-MP and TFV-DP, respectively, were validated. Accuracies were within -10.3 and 16.7% deviation at the lower limit of quantification at which the coefficients of variation were less than 18.2%. At the other tested levels accuracies were within -14.3 and 9.81% deviation and the coefficients of variation lower than 14.7%. The stability of the compounds was assessed under various analytically relevant conditions. The method was successfully applied to clinical samples.

Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

AIMS Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. METHODS We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. RESULTS Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). CONCLUSIONS We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.

An Integrated Pharmacokinetic Model for the Influence of CYP3A4 Expression on the In Vivo Disposition of Lopinavir and Its Modulation by Ritonavir

Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.

The Quantitative Effect of Serum Albumin, Serum Urea, and Valproic Acid on Unbound Phenytoin Concentrations in Children

Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.

A less sensitive detector does not necessarily result in a less sensitive method: fast quantification of 13 antiretroviral analytes in plasma with liquid chromatography coupled with tandem mass spectrometry

Abstract Background: We previously developed a method for the simultaneous determination of the human immunodeficiency protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir, the active nelfinavir metabolite M8 the non-nucleoside reverse transcriptase inhibitors efavirenz, nevirapine and etravirine and the internal standards dibenzepine, 13C6-efavirenz, D5-saquinavir and D6-indinavir in plasma using liquid chromatography coupled with tandem mass spectrometry with a Sciex API3000 triple quadrupole mass spectrometer and an analytical run time of only 10 min. We report the transfer of this method from the API3000 to a supposedly less sensitive Sciex API365 mass spectrometer. Methods: We describe the steps that were undertaken to optimize the sensitivity and validation of the method that we transferred. Results and Conclusions: We showed that transfer of a method to a putative less sensitive detector did not necessarily result in a less sensitive assay, and this method can be applied in laboratories where older mass spectrometers are available. Ultimately, the performance of the method was validated. Accuracy and precision was within 87%–110% and <13%, respectively. No notable loss in selectivity was observed. Clin Chem Lab Med 2010;48:1153–5.

Model-Informed Precision Dosing at the Bedside: Scientific Challenges and Opportunities

The development of model‐informed precision dosing (MIPD) tools, especially in the form of native or web‐based applications to be used at the bedside, has garnered marked attention in recent years. Their potential clinical benefit can be large, but it should be ensured that such tools make optimal use of available clinical data and have adequate predictive ability. Unique scientific challenges specific to MIPD remain, which may require adaptation of commonly used diagnostics in pharmacometrics.

Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure: Clinical pharmacology of HIPEC with oxaliplatin

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care in the treatment of patients with peritoneal carcinomatosis of colorectal origin. The use of oxaliplatin for HIPEC has gained popularity. Although the HIPEC procedure is adopted throughout the world, major differences exist between treatment protocols regarding the carrier solution, perfusate volume, use of an open or closed technique, duration of the perfusion and application of additional flushing. These differences can influence the pharmacokinetics and pharmacodynamics of oxaliplatin and might thereby have an impact on the efficacy and/or safety of the treatment. Clinicians should be aware of the clinical importance of oxaliplatin pharmacology when performing HIPEC surgery. This review adds new insights into the complex field of the pharmacology of HIPEC and highlights an important worldwide problem: the lack of standardization of the HIPEC procedure.