Guy Montay

A population pharmacokinetic model for docetaxel (Taxotere®): Model building and validation

A sparse sampling strategy (3 samples per patient, 521 patients) was implemented in 22 Phase 2 studies of docetaxel (Taxotere®) at the first treatment cycle for a prospective population pharmacokinetic evaluation. In addition to the 521 Phase 2 patients, 26 (data rich) patients from Phase 1 studies were included in the analysis. NONMEM analysis of an index set of 280 patients demonstrated that docetaxel clearance (CL) is related to α1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE), and body surface area (BSA). The index set population model prediction ofCL was compared to that of a naive predictor (NP) using a validation set of 267 patients. Qualitatively, the dependence ofCL onAAG, AGE, BSA, andHEP seen in the index set population model was supported in the validation set. Quantitatively, for the validation set patients overall, the performance (bias, precision) of the model was good (7 and 21%, respectively), although not better than that of theNP. However, in all the subpopulations with decreasedCL, the model performed better than theNP; the more theCL differed from the population average, the better the performance. For example, in the subpopulation of patients withAAG levels>2.27 g/L (n=26) bias and precision of model predictions were 24 and 32% vs. 53 and 53%, respectively, for theNP. The prediction ofCL using the model was better (than that of theNP) in 73% of the patients. The population model was redetermined using the whole population of 547 patients and a new covariate, albumin plasma level, was found to be a significant predictor in addition to those found previously. In the final model,HEP, AAG, andBSA are the main predictors of docetaxelCL.

Determination of Taxotere in human plasma by a semi-automated high-performance liquid chromatographic method

A rapid, selective and reproducible high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed for the determination of the anti-cancer agent Taxotere in biological fluids. The method involves a solid-phase extraction step (C2 ethyl microcolumns) using a Varian Advanced Automated Sample Processor (AASP) followed by reversed-phase HPLC. The validated quantitation range of the method is 10-2500 ng/ml in plasma with coefficients of variation < or = 11%. The method is also suitable for the determination of Taxotere in urine samples under the same conditions. The method was applied in a phase I tolerance study of Taxotere in cancer patients, allowing the pharmacokinetic profile of Taxotere to be established.

Docetaxel serum protein binding with high affinity to alpha1-acid glycoprotein

SummaryThe binding of docetaxel to human plasma proteins was studied by ultrafiltration at 37°C and pH 7.4. Docetaxel was extensively (> 98%) plasma protein bound. At clinically relevant concentrations (1–5 μg/ml), the plasma binding was concentration-independent. Lipoproteins, alpha1-acid glycoprotein and albumin were the main carriers of docetaxel in plasma, and owing to the high interindividual variability of alpha1-acid glycoprotein plasma concentration, particularly in cancer, it was concluded that alpha1-acid glycoprotein should be the main determinant of docetaxel plasma binding variability. Drugs potentially coadministered with docetaxel (cisplatin, dexamethasone, doxorubicin, etoposide, vinblastine) did not modify the plasma binding of docetaxel. In blood, docetaxel was found to be mainly located in the plasma compartment (less than 15% associated to erythrocytes).

Single‐ and Multiple‐Dose Pharmacokinetics of Riluzole in White Subjects

Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single‐ and multiple‐dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50‐mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration—time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half‐life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high‐fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng · mL−1 compared to 387 ng · mL−1) and extent of absorption (AUC = 1,047 ng · hr · mL−1 versus 1,269 ng · hr · mL−1). With multiple‐dose administration, riluzole showed dose related absorption, although the terminal plasma half‐life was prolonged slightly. Steady‐state plasma concentrations were achieved within 5 days. Steady‐state trough plasma concentrations were significantly higher with a 75‐mg dose twice daily than with a 50‐mg dose three times daily, although AUC values did not differ.

Simultaneous determination of the lactone and carboxylate forms of the camptothecin derivative CPT-11 and its metabolite SN-38 in plasma by high-performance liquid chromatography

CPT-11 (irinotecan) and mainly its metabolite SN-38 are potent antitumor derivatives of camptothecin. As the active lactone forms of both CPT-11 and SN-38 exist in pH-dependent equilibrium with their respective less potent open-ring hydroxy acid species, the simultaneous monitoring of both forms of both compounds is relevant. CPT-11 and SN-38 derivatives have quite different fluorescence responses. In order to avoid any compromise on the wavelength setting, we developed chromatographic conditions allowing simple automated wavelength setting changes which have been prevented using existing methods involving conventional C18 columns. This was achieved by means of a Symmetry C18 column combined to a gradient elution program using acetonitrile and 75 mM ammonium acetate plus 7.5 mM tetrabutylammonium bromide at pH 6.4. The developed conditions allowed an elution order suitable for a simple automated wavelength change in respect to reliable peak integration. CPT-11 and SN-38 derivatives were detected at lambda ex=362 nm/lambda em=425 nm and lambda ex=375 nm/lambda em =560 nm, respectively. The developed method allowed the detection of amounts less than 3 pg of each derivative injected on column. The method was successfully applied to pharmacokinetic and toxicokinetic studies in rat and dog.

Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis

To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS).

A Comparison of the Pharmacokinetics and Tolerability of Riluzole after Repeat Dose Administration in Healthy Elderly and Young Volunteers

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender‐ and weight‐matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half‐life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

Pharmacokinetics of Sparfloxacin in Humans After Single Oral Administration at Doses of 200, 400, 600, and 800 mg

The pharmacokinetics of sparfloxacin at oral doses of 200, 400, 600, and 800 mg were studied in 12 healthy volunteers in a randomized double‐blind crossover study. Each dose administration was separated by a 1‐week washout period. Plasma and urine samples were collected up to 120 hours postdosing, for determination of free and total (free plus glucurono‐conjugated) sparfloxacin levels by high‐performance liquid chromatography assay and ultraviolet detection. Mean Cmax values ranged from 705 ± 158 to 1966 ± 620 ng/mL for the 200 to 800 mg doses, at median tmax ranging from 4 to 5 hours. A slight decrease of sparfloxacin bioavailability with increasing dose was observed because AUC was 87% to 88% of the expected area when the dose was doubled. The elimination half‐life values were constant over the dose range (with values ranging from 18 to 21 hours) as well as the renal clearance. The metabolic ratio conjugated/free drug was not modified by increasing dose.

Pharmacokinetics and Safety of the Ketolide Telithromycin in Patients with Renal Impairment

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single‐dose study was an open‐label, nonrandomized, parallel‐group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat‐dose study was an open‐label study with a randomized, balanced, incomplete three‐block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of ≥ 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug‐related adverse events were reported. Plasma exposure to telithromycin (Cmax, AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CLCR < 30 mL/min) receiving telithromycin 800 mg in the repeat‐dose study, Cmax,ss and AUC(0–24 h)ss increased 1.5‐fold (p < 0.05) to 2.0‐fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CLR) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CLR was found to be independent of telithromycin dose in the repeat‐dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CLCR ≥ 30 mL/min). In patients with severe renal impairment (CLCR < 30 mL/min), dosage adjustment could be considered.

Pharmacokinetics of sparfloxacin in patients with renal impairment.

The pharmacokinetics of sparfloxacin were studied in 14 renal failure patients (group I, 7 with creatinine clearance of > 10 to 30 ml/min; and group II, 7 with creatinine clearance of < or = 10 ml/min) after a single oral dose of 400 mg. Plasma and urine samples were collected up to 144 h postdosing for determination of parent and total (parent-plus-glucuronide-conjugated) sparfloxacin levels, by high-pressure liquid chromatography assay and UV detection. The elimination of the drug in patients compared with that in healthy volunteers was markedly impaired. The mean elimination half-lives of sparfloxacin were 34.9 and 38.5 h in group I and group II, respectively, versus 19.1 h in healthy volunteers. Conjugated drug half-lives were 23.7, 35.0, and 15.3 h, respectively. The renal clearance of the drug was markedly reduced in the patients, with values of 6.8, 4.8, and 21.2 ml/min determined for group I, group II, and healthy subjects, respectively, for parent sparfloxacin and with values of 31.5, 14.0, and 327 ml/min for conjugated sparfloxacin. The nonrenal clearance of sparfloxacin was moderately, but not significantly, decreased in group II renal failure patients. No difference between the two groups of patients was detected in sparfloxacin levels in plasma. A significant relationship between pharmacokinetic parameters and creatinine clearance was observed only for renal clearance of parent or conjugated sparfloxacin.