Traditional medicine consumption in postpartum for HBV-infected women enrolled in the ANRS 12345 TA PROHM study in Cambodia.

In Cambodia, traditional medicine was commonly described as being used by pregnant women at two time points: one month before birth and during early postpartum. The present study aims to describe traditional medicine consumption during postpartum phase for women enrolled in the TA PROHM study and to investigate the possible association between traditional medicine consumption and acute liver toxicity. An ethnobotanical survey was conducted in 2 groups of HBV-infected pregnant women (with and without postpartum hepatocellular injury) enrolled in the study. Hepatocellular injury was defined by having Alanine Aminotransferase (ALT) > 2.5 times the Upper Limit of Normal (ULN = 40 U/L) at the 6th week postpartum visit. Interviews were done using a standardized questionnaire. Plant samples were collected and later identified by two traditional healers. Chi-square test was used to find the association between hepatocellular injury and traditional medicine consumption or a specific plant species. In total, 75 women were enrolled and 52 (69.3%) used at least one traditional remedy composed of 123 different plants and 12 alcoholic macerations of porcupine stomach. Orally consuming at least one remedy with alcohol was significantly associated with hepatocellular injury (33% vs 13%, p = 0.034). Among the 123 plants species identified, four were found to be associated with hepatocellular injury, namely Amphineurion marginatum (Roxb.) D.J.Middleton [Apocynaceae] (p = 0.022), Selaginella tamariscina (P.Beauv.) Spring [Selaginellaceae] (p = 0.048), Mitragyna speciosa Korth. [Rubiaceae] (p = 0.099) and Tetracera indica (Christm. & Panz.) Merr. [Dilleniaceae] (p = 0.079). Consumption of traditional medicine in postpartum is a common practice for women enrolled in the TA PROHM study. Alcohol-based remedies may exacerbate the risk of acute hepatocellular injury in HBV-infected women already exposed to immune restoration. The complex mixtures of herbs need to be further evaluated by in vitro and in vivo studies.

Multicentric phase II trial of TI-CE high-dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors.

BACKGROUND: High-dose chemotherapy (HDCT) with TI-CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug. METHODS: Patients with unfavorable relapsed GCT were treated according to TI-CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate. RESULTS: Eighty-nine patients who received HDCT were included in the modified intent-to-treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty-five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow-up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5-25.9) and OS was 46.3 m (95% CI: 18.6-not reached). For high- and very high-risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2-year PFS rate was 41.1%. CONCLUSION: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors.

BACKGROUND: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol. METHODS: Eighty-eight patients received 400 mg/m2/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated. RESULTS: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation. CONCLUSIONS: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.

Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring.

BACKGROUND: Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations. METHODS: U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU. RESULTS: The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%]. CONCLUSIONS: The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.

Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study.

Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug-drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120-150 mg/m2 day 1-2-3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug-drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study.

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative.Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction.Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83)-0.826 × (BW/76)+0.907 × (Age/36)-0.223 with Scr in µmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations.Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171-9. ©2017 AACR.