M. Tod, C. Pobel, O. Petitjean, N. Brion, J. Garcia-Mace
Departement de pharmacotoxicologie, Hôpital Avicenne, Bobigny 93009 and Versus, Paris, 75009 and Laboratoire Bouchara, 92300 Levallois, France.
The pharmacokinetics of alminoprofen in plasma and in synovial fluid was studied in 45 subjects (11 women and 34 men) with knee effusions but in otherwise good health. Their mean ± SD age was 41 ± 17 years. They received 300 mg of Minalfen® TID (at 7h, 15h and 23h) and the patients were sampled after the 13th dose. In each patient, a blood sample and a synovial sample were taken simultaneously. Six groups of patients were made according to the time of sampling after the last dose : 1h (n = 7), 2h (n = 7), 4h (n = 7), 6h (n = 10), 8h (n = 6), 12h (n = 8). Alminoprofen was determined by liquid chromatography. Several covariables were recorded : height, wheight, albumine and creatinine in serum, interleukine 6 in synovial fluid. The data were analyzed by NONMEM version III. A 2-compartment pharmacokinetic model was chosen to describe the concentration in plasma (central compartment) and in synovial fluid (peripheral compartment) and the model was parametrized in terms of microconstants : Ke = elimination rate constant, Ka = absorption rate constant, Kcp and Kpc = transfer rate constants and Vd = volume of the central compartment. An exponential error model was used for intra and interindividual variability. The option of estimating the covariances between parameters was omitted. Linear relations between pharmacokinetic parameters and covariables were explored and tested by usual criteria (likelihood ratio test, SE of estimates, scatter plots). The results were as follows (point estimate ± SE, CV = coefficient of variation):
|
| Ke (h-1) | kcp (h-1) | kpc(h-1) | Vd(L) | Ka (h-1) |
| Mean | 0.236 | 0.0102 | 0.249 | 11.0 | 2.80 |
|
| ± 0.025 | ± 0.0048 | ± 0.097 | ± 1.7 | ±0.31 |
| CV interindiv. (%) | 18 ±2 | 37 ±9 | 32 ±5 | 12 ±9 | 464 ± 1850 |
The CV of the residual error was 4.0 ± 0.5 % and was similar to that of the analytical precision. No significant correlations were found between the parameters and the covariables. The mean ± SE experimental Cmax was 24.2 ± 4.8 mg/1 in plasma (Tmax = 1h) and 9.3 ± 1.8 mg/1 in synovial fluid (Tmax = 2h). This study confirmed the fast and high penetration of alminoprofen in synovial fluid with relatively moderate interindividual variability.
Reference: PAGE 3 () Abstr 860 [www.page-meeting.org/?abstract=860]
Poster: poster