Methadone is an opiate drug that has been identified as an in-vitro substrate of the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in the blood-brain barrier (BBB), among other sites. The objective of this study was to test in vivo, in the rat model, the role of P-gp modulation on the analgesic effect and brain uptake of methadone, as well as identify the most relevant site via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor (valspodar or PSC833) was preadministered (10 mg kg(-1) i.v.) to test groups. Analgesia was measured using the tailflick test. The ED50 for oral methadone (2, 3, 6 and 8 mg kg(-1)) decreased three-fold in valspodar groups compared with controls (2.23 +/- 0.002 mg kg(-1) and 6.07 +/- 0.07 mg kg(-1); P < 0.0001). The overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated compared with control rats (90.65% +/- 0.22 vs 29.23% +/- 14.0; P < 0.01) after 6 mg kg(-1) oral methadone and 2.8 times after i.v. (0.35 mg kg(-1)) administration (91.75% +/- 4.27 vs 32.45% +/- 9.0; P < 0.01). The brain:plasma distribution ratio was higher in pretreated animals and AUCbrain (overall brain concentration) was 6 times higher after oral methadone and 4 times higher after i.v. compared with controls, disproportionally increased relative to plasma, implying an active process at the BBB. P-gp, and hence substrate comedication, plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route.

For TAC therapy, covariate models using mixed effects methods are most useful when combined with patient-specific biochemical assays as well as clinical evidence. In such cases, the observed C(min) and Bayes methods can provide the most likely individual PK parameters, hence the optimal next dose to reach individualized target levels for each patient.

Due to the absence of significant changes in the protein binding it is unlikely that there will be an exaggerated pharmacological response in patients with renal and hepatic disease following the administration of a standard propofol dose, although due to interpatient variability careful titration can be recommended.

Purpose The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto® -ReFacto ) in HIV+ vs. HIVpatients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods. Methods Twenty-eight haemophilia A adults (20 HIV-and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV-/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000-4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and lifethreatening haemorrhages. Results One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL)=2.56 dl h −1 (33.2%); volume of distribution (V)=34.8 dl (12.8%); and for OSC: CL= 3.83 dl h −1 (47.8%), V=53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p<0.0001), and variabilities were higher for OSC. Nevertheless, the empirical half-lives (t 1/2 =l n (2) × V/CL) were similar for CHS and OSC, [(mean ± standard deviation (SD)], 9.5 ± 3 h and 10.2 ± 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p<0.005) for V.The final covariate models with OSC were for CL=3.93 + 0.09 × (WT-75) and for V=48.6 × (1 + 0.36 × VIR) + 0.55 × (WT-75); therefore, V for the typical HIV+ patient was 36% higher than for the HIV-patient. Conclusions Both HIV-and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIVpatients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV-patient equivalent to have the same probability of success.

In conclusion, in these critically ill patients, an increase in the percentage of free propofol occurs. The significance of this observation remains uncertain, but may be validated in future studies. However, the observation supports the common idea that potent drugs should be given with great care in critically ill patients.