Optimal sampling strategies for bayesian estimation of docetaxel (Taxotere) clearance.

Docetaxel activity has been documented in many solid tumors, including metastatic breast cancer and non-small cell lung cancer. However, as clinical studies in other tumor types are now being conducted, the validation of an optimal sampling strategy would allow the performance of pharmacokinetics/pharmacodynamics studies with minimum inconvenience for the patient. Six optimal sampling strategies with one to six sampling times were computed, based on the D-optimality theory, using population pharmacokinetic parameters estimated from a large pharmacokinetic database of 547 patients treated in previous Phase II studies. Validation of these sampling strategies was performed on a set of 35 patients, from two Phase I studies, who received docetaxel as a 1-h infusion at doses ranging from 50 to 100 mg/m2. Validation consisted of comparing clearance assessed by maximum likelihood estimation obtained using complete plasma concentration-time data (considered as the reference) and clearance determined by Bayesian estimation with an optimal design. For all of the optimal sampling strategies tested, clearance was found to be well estimated when at least two samples were taken. Bayesian estimation with two measured levels (at the end of infusion and at 6 h after the start of infusion) can be selected, because it allows adequate estimation of clearance with a nonsignificant bias of +1.37% and a precision of 12.3%.

A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma.

The aim of this study was to evaluate the efficacy of docetaxel as first-line chemotherapy in patients with unresectable metastatic or locally advanced pancreatic adenocarcinoma and to further characterise the safety and pharmacokinetic profiles of docetaxel. 43 patients were enrolled into this phase II study. Treatment consisted of a 1-h infusion of docetaxel 100 mg/m2 every 3 weeks without premedication with corticosteroids until progression or unacceptable toxicity occurred. Dose modifications were planned for adverse events. Patients were observed for 1 month after the last docetaxel infusion, to document any late adverse events, with a follow-up every 3 months until death. Response rate and duration were the major efficacy endpoints. Response status was reviewed by an external independent panel. Pharmacokinetic analysis was performed during the first treatment cycle. 40 patients were evaluable for response, and all were evaluable for safety. After independent review, partial response was recorded in 6 patients (overall response rate, 15%; 95% confidence limit (CI), 7.7-29.8%) and stable disease was recorded in 15 patients (38%). The median duration of response was 5.1 months (range: 3.1-7.2). The median pain control time was 4.5 months (range: 0-8) and the median time to performance status worsening was 2.3 months (range: 0-4.5). Most patients 40 (93.0%) received a relative dose intensity of more than 70% of the planned dose. The incidence and severity of adverse events reflected the known safety profile for docetaxel. Docetaxel clearance was reduced in patients with elevated concentrations of hepatic enzymes or bilirubin. Docetaxel is an active agent for unresectable metastatic or locally advanced pancreatic adenocarcinoma.

Which bioequivalence study for a racemic drug? Application to milnacipran.

Milnacipran, a new non tricyclic antidepressant drug, is a racemic mixture (F2207) composed of two enantiomers: F2695 and F2696, both demonstrated to be active. A randomized open label, single-dose latin square study was undertaken in 24 healthy volunteers to compare, based on racemate data, the relative bioavailability of two new formulations to that of a reference formulation. Later on, as suggested by actual regulatory trend, analysis was carried out on enantiomer data, although in a supportive way. Bioequivalence was assessed on calculation of 90% confidence intervals for log-transformed Cmax and AUC(0-infinity) and on Wilcoxon test for Tmax with a 5% level of significance. Based on racemate data, both test formulations were demonstrated to be equivalent to the reference capsule in terms of Cmax and AUC-(0-infinity). Differences in Tmax reached statistical significance, although their mean magnitude was small, and probably not relevant when related to antidepressant long-term therapy. When considering the test capsule - reference capsule comparison, the equivalence demonstrated for the racemate reflect that of each enantiomer. On the contrary, equivalence between the test tablet and the reference capsule demonstrated for the racemate, is not supported by both enantiomers as Cmax of F2696 fails to reach bioequivalence criteria, making more uncertain the conclusion of bioequivalence. From this experience, it seems than when equivalence is demonstrated close to the limits for the racemate, it is difficult, especially for a low variability drug such as milnacipran, to comply with equivalence criteria for both enantiomers.

Pharmacokinetics of milnacipran in renal impairment.

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.