Altered dose-to-effect of propofol due to pharmacokinetics in rats with experimental diabetes mellitus.

Pathology related alterations in the pharmacokinetics or the pharmacodynamics of propofol could contribute to the observed large variability in the hypnotic dose. We have tested the influence of diabetes mellitus on the induction dose and the pharmacokinetics and pharmacodynamics of propofol in rats. Diabetes was induced in rats by administration of streptozotocin (60 mg kg(-1), i. p.) while control rats received vehicle intraperitoneally. All animals had glucose, cholesterol, triglycerides and albumin levels measured. In-vitro protein binding was determined by ultrafiltration. Rats were randomly split into set 1 (dose-concentration-effect study) with control and streptozotocin rats, and set 2 (pharmacokinetic study), with control and streptozotocin rats. Rats in the effect set received either a variable infusion of 6 mg kg(-1) min(-1) propofol until onset (induction dose) of the hypnotic effect (loss of the righting reflex), or a 15 mg kg(-1) bolus to assess offset time (recovery of the righting reflex). Blood (C(blood)) and brain (C(brain)) propofol concentrations at onset and offset were assayed by HPLC. In the pharmacokinetic study, propofol was administered intravenously at 6 mg kg(-1) min(-1) for 2 min. Arterial blood samples were collected between 0.5 and 540 min and assayed for propofol. A mixed effects compartmental pharmacokinetic modelling method (NONMEM) was used to analyse the observations and variabilities. The dose necessary for onset differed between streptozotocin and controls, and so did the pharmacokinetics with two- and three-compartment descriptions, respectively. C(blood) and C(brain) at onset and offset were similar, possibly rejecting changes in pharmacodynamics. The total and unbound volume of distribution was significantly lower in the streptozotocin group with no differences in clearance (CL) between streptozotocin and controls, (mean (inter-animal CV%)) CL = 0.026 (17%) and 0.025 (62%) L min(-1), respectively. Individual Bayes Vd(ss) (volume of distribution at steady state) were different, (mean (s. d.)) Vd(ss) = 7.7 (2.67) and 1.11 (0.09) L, respectively. The pharmacokinetic model was validated by comparison with the data from set 1. Simulations of total and unbound C(blood), for both groups, at the hypnotic dose for the controls, revealed differences throughout the time course of the pharmacokinetics. The difference observed in the induction dose of propofol to streptozotocin and control rats was due to alterations in the pharmacokinetics, secondary to the pathology.

Impact of poor compliance with levofloxacin and moxifloxacin on respiratory tract infection antimicrobial efficacy: a pharmacokinetic/pharmacodynamic simulation study.

The purpose of this report was to assess the impact of poor compliance on the efficacy of levofloxacin (LFX) and moxifloxacin (MOX), two fluoroquinolones with different pharmacokinetic (PK) and pharmacodynamic (PD) properties, in respiratory infections. The fAUC0-24h and fAUC0-24h/MIC90 ratio, a PK/PD index predictive of bacterial eradication, were extracted from previously described population PK models for LFX and MOX. The MIC90 was according to EUCAST. Monte Carlo simulations were used with LFX 500 mg every 24h (q24 h) or every 12h (q12h), LFX 750 mg q24 h and MOX 400mg q24 h in non-compliance scenarios to derive the proportion of patients achieving target ratios of fAUC0-24h/MIC90>33.8 for Streptococcus pneumoniae and >100 for Haemophilus influenzae and Moraxella catarrhalis (PTA>90%). In non-adherent dosing scenarios, LFX 500 mg q24 h was not able to reach the PK/PD index guaranteeing clinical efficacy. With LFX 500 mg q12 h or 750 mg q24 h, this probability was maintained although patients can take the dose with delays of up to 12h and 11h, respectively, for the three bacterial types. With MOX 400mg q24 h, the probability of achieving this PK/PD index is maintained with delay in dosing up to 16h. In conclusion, LFX 500 mg q24 h is the least robust treatment against S. pneumoniae, H. influenzae and M. catarrhalis in a non-adherence situation. A good choice is LFX 500 mg q12h, but in order to favour patient adherence, LFX 750 mg q24 h or MOX 400mg q24h appears as more appropriate.

Time-dependent pharmacokinetics of cyclosporine (Neoral) in de novo renal transplant patients.

PURPOSE: A model for the large scale temporal trend in the oral bioavailability of microemulsion cyclosporine (Neoral) (CsA) is established, with dependence on post-(renal) transplantation day (PTD). METHODS: Twenty de novo adult renal transplant recipients were monitored for CsA administered orally q12 h. A model development group (11 patients, 315 blood concentration samples) was screened at 2 h (C(2); n = 92), 3 h (C(3); n = 56) and at predose troughs (C(min); n = 167) over periods of up to 75 days. The final model was tested in nine patients with C(min) (n = 580) monitored across 4-5 years. The doses varied between 100 and 538 mg with an apparent hyperbolic trend in C(2)/dose vs. PTD. A nonlinear mixed effects modelling (NONMEM) approach was used to obtain population and individual patient one-compartment pharmacokinetic (PK) parameters for oral CsA, which carry implicit the bioavailability (F). RESULTS: In the final PK model (PK-f) the F was modelled via a simple function for the temporal (days) trend of the bioavailability after transplantation as, F(f) = 1-alpha * exp(-lambda * PTD) resulting in a 28% reduction in the unexplained intra-individual variability. The population PK-f parameters were, for apparent clearance [mean, 95% confidence interval (interindividual CV%)] Cl/F(f) = 17.0 (13.8-20.2) L/h (27%), apparent central compartment volume of distribution, V/F(f) = 134 L (108-160) (28%), and lambda = 0.037/day (0.005-0.069) (120%). The absorption rate k(a) and the parameter alpha were approximated iteratively as 4/h and 0.62 respectively. The PK-f was structurally superior to the base model in explaining part of the within subject (occasion) variability and predicting the exposure surrogates C(2) and C(3). Also, the PK-f was better than the base model with Bayesian fitting of individual profiles in that group. CONCLUSION: The PTD-dependent relative bioavailability model provides a rational means of steering dose titration of CsA in de novo renal transplantation patients by removing the large scale PK adjustment signal, either through nomograms or as a Bayesian prior.

Altered disposition and effect of lerisetron in rats with elevated alpha 1-acid glycoprotein levels.

PURPOSE: To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat. METHODS: After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.v.) 14C lerisetron (50 microg/kg) in control and turpentine oil pretreated rats. The PK (0-180 min) was described by a two-compartmental model. Protein binding of lerisetron in vitro was measured using an ultrafiltration technique. The effect of lerisetron (5 microg/kg, i.v.) over 180 min was measured in anesthetized rats (control and pretreated) with the Bezold-Jarisch reflex (inhibition of bradycardia after 16 microg/kg serotonin i.v.) as the endpoint. PD parameters were estimated by sigmoid Emax models. RESULTS: The unbound fraction was significantly diminished in pretreated rats (mean +/- SEM) (6.60 +/- 1.23% vs. control 14.4 +/- 1.40%, P < 0.05). Volume of distribution (V) and clearance for UL and TL were significantly decreased when compared to the controls (P < 0.0001 for UL and P < 0.05 for TL). Plasma clearance based on unbound concentration for UL did not differ between groups but the unbound V and steady-state unbound V remained decreased (P < 0.05 and P < 0.0001). Pretreated rats showed a significantly diminished drug effect: the area under the E-t curve over 180 min was (mean +/- SEM) 5,189 +/- 657.7 in control animals vs. 3,486 +/- 464.4 in the pretreated group (P < 0.05). The EC50 (concentration at half maximum effect) for UL and TL were increased in pretreated rats and were not compensated when the unbound concentration was used. CONCLUSIONS: An increase in AAG causes alterations in the PK and PD of lerisetron, and because this is not compensated with the unbound concentration, we suggest that mechanisms not linked to protein binding may be involved.

Intrauterine growth retardation after long-term maternal salicylate administration in the rabbit.

The effects of chronic maternal salicylism on fetal growth were studied in chronically catheterized pregnant rabbits. Graded intravenous infusions of sodium salicylate were given continuously between days 22 and 29 of gestation. Maternal plasma salicylate concentrations (mean +/- SD) of 12.0 +/- 1.6 mg/dl (low-dose group) or 24.1 +/- 5.3 mg/dl (high-dose group) were achieved. Control rabbits were infused with saline solution. Pups were delivered by hysterotomy on day 29. Fetal/maternal salicylate concentration ratios were near unity for both infusion groups. There were significant dose-related reductions (mean +/- SD) in fetal weight (control, 39.7 +/- 6.7 gm; low-dose group, 34.4 +/- 6.4 gm; high-dose group, 22.2 +/- 7.1 gm; p less than 0.001) and in crown-rump length (control, 9.7 +/- 0.45 cm; low-dose group, 9.1 +/- 0.68 cm; high-dose group, 7.7 +/- 0.86 cm; p less than 0.001). There was a significant reduction in fetal brain weight only in the high-dose group, and brain weight/fetal weight ratios were increased, suggesting relative sparing of brain growth. Liver weight was significantly reduced in both low- and high-dose groups. In contrast to results in previous animal studies, standardized intravenous maternal salicylate administration in rabbits induced a reproducible and dose-dependent asymmetrical fetal growth retardation.

Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients.

BACKGROUND: In anesthesia with propofol, variability persists besides sophisticated effect targeting. Drug formulation may be another factor. We have analyzed, retrospectively, the pharmacokinetics (PK) and pharmacodynamics (PD) in monitored surgery patients anesthetized with one each of five formulations of propofol. METHODS: Propofol 1% ('form' 1: Diprivan(Zeneca Limited, Macclesfield, UK), 2: Recofol(Schering Espana, Madrid, Spain), 3: Ivofol(Juste, Madrid, Spain), 4: Propofol Abbott (Abbott Laboratories, Madrid, Spain), 5: Fresenius (Fresenius Kabi Espana, Barcelona, Spain)) was administered to 77 ASA I-II patients of age [mean (range) 44 (18-65) years]. Induction of anesthesia was with varying propofol doses up to endpoints of either 60 on the Bispectral Index system (BIS) in group I (n = 48, model development) or standard clinical signs in group II (n = 29, validation). Maintenance was with three 10-min infusions of 10, 8 and 6 mg kg(-1) h(-1). Three blood samples were obtained from each subject, immediately after induction, and at 15 and 30 min on maintenance, with BIS and hemodynamic variables recorded at these times also. Total and free blood concentrations (Cb) of propofol were determined with HPLC. Pharmacokinetic and PD models with link equilibration rate ke0, were studied with a mixed-effects procedure (NONMEM). RESULTS: The induction dose (group I) showed large interindividual variability [mean (range) 163 (90-290 mg)] that correlated significantly with age, basal systolic blood pressure and formulation. The PK of propofol (basic model) was described by a one-compartment model with (typical value [interindividual coefficient of variation percent (CV%)]) CL=2.30 l min(-1) (27%) and V=8.40 l (80%). Weight (WT) and formulation, within NONMEM, were found to be significant covariates for CL and V, reducing their CV% to 25% and 74%, respectively. The final PK/PD model, which includes formulation, showed a 50% reduction in the CV% for both the ke0 and the residual error. This PK/PD model was validated in group II with 33% precision and no bias. CONCLUSION: The PK and PD are not equal for all formulations, which contributes to an increase in variability of the observed effect.