Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Effects of demographic variables on vorozole pharmacokinetics in healthy volunteers and in breast cancer patients.

PURPOSE: Vorozole (VOR) is a selective nonsteroidal inhibitor of the cytochrome P450-dependent aromatase that catalyzes the conversion of androgens to estrogens. It is currently being developed as a therapeutic agent in the endocrine treatment of postmenopausal women with breast cancer. This work was aimed to explore the effects of demographic and other variables on VOR pharmacokinetics. METHODS: VOR plasma concentration-time data were obtained in healthy volunteers and in breast cancer patients after the oral administration of 2.5 mg of VOR as a single dose or once daily. The data obtained in 6 formal pharmacokinetics (PK) studies with frequent plasma sampling were included in the data base (84 healthy male and female volunteers and 13 breast cancer patients). Also included were data from 2 clinical efficacy trials involving 286 breast cancer patients who were treated for several months (1 sample per visit, up to 14 samples/patient). The nonlinear mixed-effect modeling (NONMEM) approach was applied. The two-compartment linear PK model with first-order absorption parameterized in terms of apparent clearance (CL), apparent central and peripheral volumes of distribution (Vc and Vp, respectively), apparent distributional flow (Q), and absorption constant (ka) was used. A population model was developed using data from formal PK studies. The final estimates of fixed and random effect parameters were obtained using both formal study data and clinical-efficacy trial data. RESULTS: The typical CL value obtained after a single dose was lower in patients (4.8 l/h) as compared with healthy volunteers (8.6 l/h) and did not depend on gender. The multiple- to single-dose ratio was 0.76. CL was constant over ages of up to 50 years and then decreased slightly (0.047 l/h per year). The typical CL value did not depend on any demographic variable related to body size (total body weight, WT; body surface area; lean body mass). Q and Vc were proportional to WT (0.17 l h(-1) kg(-1) and 0.43 l/kg, respectively). Vp was also proportional to WT and was higher in women as compared with men (0.64 and 0.40 l/kg, respectively). The same was true for the apparent steady-state volume of distribution. No effect of race or the duration of therapy (0.5-28 months) was seen. The unexplained variability in CL and the residual variability in VOR plasma concentrations were 39% and 28% (coefficient of variation), respectively. CONCLUSIONS: Healthy volunteer/patient, single/multiple dosing differences, and age were identified as the fixed effects influencing the CL of VOR. WT was the main determinant of distributional PK parameters. The peripheral and steady-state volumes of distribution were gender-dependent. In view of the relatively high degree of residual interpatient variability in CL, the slight effect of age on it is unlikely to be clinically significant.

Indirect pharmacodynamic response models do not require any parametric pharmacokinetic model to be fitted to effect-time data.

Indirect response models (IRM) represent one of the possible ways to explain and quantitatively describe a delayed pharmacodynamic effect at non-steady-state conditions. The standard way to get estimates of pharmacodynamic (PD) parameters of IRM consists of two steps. First, an appropriate parametric pharmacokinetic (PK) model (compartmental, polyexponential, etc.) is to be fitted to plasma concentration-time data, and then IRM is fitted to PD data having PD model as an input. In the present work it is demonstrated that a simple piecewise function which consists in interpolation lines connecting concentration-time points can be used as a universal nonparametric PK model thereby allowing to skip the first step. MS Excel spreadsheets implementing this PK model and four known versions of IRM are presented. The usefulness of the approach is demonstrated by fitting IRMs to simulated data as well as to real PK/PD data of warfarin and terbutaline. Estimates of IRM parameters obtained with the nonparametric PK model were close to that published in the literature.

Population pharmacodynamic and pharmacokinetic modeling via mixed effects.

Pharmacokinetics (PK) and pharmacodynamics (PD) are two scientific disciplines forming the basis of modern pharmaco- and chemotherapy. PK reflects what the body does to drugs and primarily deals with plasma concentration of drugs, whereas PD reflects what drugs do to the body, focusing on time-courses of responses produced by drugs. PK-PD modeling is a mathematical tool, which is used to establish a quantitative relationship between PK and PD. Population PK and PD modeling is aimed to quantify inter- and intra-individual variability in drug concentrations and responses, respectively. This review will attempt to summarize the progress in population PK and PD modeling over the last five years. Mixed-effects modeling is a statistical tool which makes population PK-PD analysis feasible, and this review sheds some light on basic ideas and applications of this powerful method without using complicated mathematics and statistics. Major concepts, approaches and methods are introduced on the basis of simplified examples that make these understandable for readers not involved in PK-PD modeling.