Probabilistic risk analysis: improving early drug development decision making.

Model-based drug development (MBDD) is advocated by industry, academia, and regulatory agencies as a powerful tool to improve the efficiency of drug development. Clinical pharmacologists play key roles in implementing MBDD because of their ability to integrate mechanistic, preclinical, and clinical information, using quantitative approaches to address the complex questions arising during drug development. Use of probabilistic risk analysis (PRA) approaches (e.g., value of information, combining uncertain information, and modeling expert opinion) can improve the implementation of MBDD.

Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours.

A phase I, repeat-dose, open-label study was conducted to determine the pharmacokinetics and safety of zidovudine and lamivudine, coadministered orally every 12 hours, in 16 neonates whose mothers were infected with human immunodeficiency virus type 1 (HIV-1). The prospective mothers had been stabilized on a zidovudine/lamivudine regimen since week 36 of pregnancy to prevent mother-to-child transmission of HIV. During 1 week postpartum, the mothers received zidovudine 300 mg plus lamivudine 150 mg every 12 hours and breastfed. Neonatal treatment was initiated 12 hours following birth with 4 mg/kg of zidovudine suspension plus 2 mg/kg of lamivudine solution every 12 hours; this regimen was continued for 1 week. Between days 1 and 7 of neonatal treatment, the neonatal oral clearance (CL/F) of zidovudine and lamivudine increased by 2-fold (p < 0.001) and 1.6-fold (p = 0.004), respectively, possibly reflecting maturation of intestinal hepatic and renal function occurring during the first week of life. Day 7/day 1 ratios for exposure (area under the serum concentration-time curve [AUC]) and maximum observed serum concentration (Cmax) were 0.48 and 0.63, respectively, for zidovudine and 0.64 and 0.73, respectively, for lamivudine. At the time of delivery, the geometric mean cord/maternal concentration ratio was 1.24 for zidovudine and 1.12 for lamivudine, indicating free passage of each drug across the placenta. The maternal and neonatal treatment regimens were well tolerated. The results of this study confirm that in the neonate, a convenient regimen combining zidovudine 4 mg/kg and lamivudine 2 mg/kg, administered orally every 12 hours, provides zidovudine serum exposure very similar to that reported with the standard neonatal zidovudine regimen of 2 mg/kg every 6 hours, as well as lamivudine serum exposure within the range reported in adults receiving lamivudine 150 mg twice a day and children receiving 4 mg/kg twice a day.

Phase I trial of a 96 h paclitaxel infusion with filgrastim support in refractory solid tumor patients.

A phase I study of a 96 h paclitaxel infusion with filgrastim support was performed to determine the toxicity, maximum-tolerated dose (MTD) and pharmacokinetics in patients with refractory solid tumors. In this phase I trial, the initial paclitaxel dose was 140 mg/m2/96 h followed by filgrastim (5 microg/kg/day s.c.) beginning 24 h after the paclitaxel and continued until granulocyte recovery. Cycles were repeated every 21 days. Patients with refractory solid tumors were eligible; however, only one previous chemotherapy regimen was allowed. The dose of paclitaxel was escalated by 20 mg/m2/96 h in subsequent cohorts until dose-limiting toxicity (DLT) occurred. Pharmacokinetic analysis was performed by quantitating paclitaxel concentrations at baseline, 24, 48, 72 and 96 h after the start of the paclitaxel infusion. Twenty-one patients were entered into this trial of which 19 were evaluable. A total of 52 treatment cycles were administered. DLT was seen in two of four patients at 200 mg/m2/96 h, and consisted of diarrhea, mucositis and granulocytopenic infection. The MTD of the 96 h paclitaxel infusion was 180 mg/m2 with filgrastim support. Mucosal and granulocyte toxicity were correlated with steady-state paclitaxel concentrations (Css) greater than 0.100 micromol/l. In the presence of liver function test 1.5 times or lower than normal, metastatic liver disease did not alter paclitaxel Css. Objective responses were observed in non-small cell lung cancer, small cell lung cancer and melanoma. The recommended phase II dose of paclitaxel infused over 96 h with filgrastim support is 180 mg/m2. Paclitaxel Css correlate with mucosal and granulocyte toxicity. In the presence of normal enzymatic function, metastatic liver disease does not affect paclitaxel clearance.