Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis.

WHAT IS KNOWN AND OBJECTIVE: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. METHODS: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model. RESULTS AND DISCUSSION: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume V(d)/F = 50·1 L (1·29 as high for males), absorption rate constant K(aA) = 0·391/h, K(aB,C,D) = 2·70/h, relative bioavailability F(A) = 0·468, F(B,C,D) = 1, lag time in the absorption phase T(lag) = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, V(d) /F and K(a) by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%. WHAT IS NEW AND CONCLUSION: Gender was associated with changes in CL/F and V(d) /F whereas the pharmaceutical formulation was associated with changes in F and altered the K(a) . The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.

Relative bioavailability of rifampicin in a three-drug fixed-dose combination formulation.

SETTING: In a previous monitoring study of rifampicin (RMP) in tuberculosis (TB) patients treated with a generic formulation of a three-drug fixed-dose combination (3FDC), very low RMP levels were found. This led us to investigate the bioavailability of the product. OBJECTIVE: To investigate the relative bioavailability of RMP from a generic 3FDC formulation used in the Mexican health care system, in comparison to the reference product, in healthy volunteers. DESIGN: Two-period, two-sequence crossover study. RESULTS: Mean pharmacokinetic parameter values obtained for the test and reference product were respectively 3.13 ± 2.01 µg/ml and 9.95 ± 2.66 µg/ml for peak plasma concentration (C(max)), 15.51 ± 9.77 µg.h/ml and 58.03 ± 16.1 µg.h/ml for area under the concentration (AUC) time curve to the last measurable concentration (AUC(0-12h)) and 17.92 ± 10.66 and 68.43 ± 22.39 µg.h/ml for AUC up to time infinity (AUC(0-∞)). The test/reference ratio of the means (90%CI) was 25.36% (17.33-37.10) for C(max), 21.25% (14.61-30.89) for AUC(0-12h) and 22.08% (15.44-31.56) for AUC(0-∞). These results did not meet the criteria for bioequivalence. CONCLUSION: The test product displayed delayed absorption and markedly inferior RMP bioavailability in comparison to the reference product. RMP-containing generic formulations should only be used if their bioavailability has been evaluated to ensure interchangeability with the reference product and to avoid the risk of markedly inferior RMP exposure through the use of such a product.

Effect of caffeine on antinociceptive action of ketoprofen in rats.

BACKGROUND: To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain. METHODS: Antinociceptive activity was assayed using "ellipsis pain-induced functional impairment in the rat" (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations). RESULTS: ASA (ED(50) 465.2 +/- 1.5 mg/kg), MOR (ED(50) 71.0 +/- 1.6 mg/kg), and KET (ED(50) 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 +/- 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effective dose (ED(50)) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED(50) of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF. CONCLUSIONS: These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.