Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites.

The anticancer drug ifosfamide is a prodrug requiring activation through 4-hydroxyifosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of ifosfamide leads to 2- and 3-dechloroethylifosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for ifosfamide and increased for 3-dechloroethylifosfamide compared with short infusion durations. No differences in dose-normalized exposure to ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylifosfamide. The observed dose and infusion duration dependence should be taken into account when modeling ifosfamide metabolism.     

Distribution of ifosfamide and metabolites between plasma and erythrocytes.

The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m(2)/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (+/-sem) in vitro and in vivo erythrocyte (e)-plasma (p) partition coefficients (P(e/p)) were 0.75+/-0.01 and 0.81+/-0.03, 0.62+/-0.09 and 0.73+/-0.05, 0.76+/-0.10 and 0.93+/-0.05 and 1.38+/-0.04 and 0.98+/-0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUC(e/p)) were 0.96+/-0.03, 0.87+/-0.07, 0.98+/-0.06 and 1.34+/-0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies.     

Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM

AIMS: This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m-2 ifosfamide by means of a 72 h continuous i.v. infusion. METHODS: A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction. RESULTS: The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 +/- 0.27 l h-1, 43.5 +/- 2.9 l, 0.0546 +/- 0. 0078 h-1, 12.7 h and 30.7 +/- 4.8 microM, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 microM, respectively. CONCLUSIONS: The absence of a lag time for the autoinduction of ifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients.     

Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxylated metabolites in children with malignant disease: a sparse sampling approach

OBJECTIVE: To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. DESIGN: Pharmacokinetic assessment followed by model fitting. Patients: The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. METHODS: A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. RESULTS: Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. CONCLUSIONS: We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.     

Differential in vitro hepatic and intestinal metabolism of ifosfamide in the rat

1. Metabolism of ifosfamide (IF) in intestinal and hepatic microsomes has been investigated in the rat. The generation of three primary metabolites, 4-hydroxyifosfamide (HOIF), N2-dechloroethylifosfamide(N2D) and N3-dechloroethylifosfamide (N3D),was followed. 2. Microflora in rat small intestine showed no metabolic activity towards IF. The overall metabolic activity was higher in the hepatic microsomes than in the intestinal microsomes, and the hydroxylation pathway accounted for 53.6% of total IF metabolism in the hepatic microsomes. In contrast, hydroxylation of IF in intestinal microsomes was only 9.8% of the total monitored metabolic activity and N3-dechloroethylation of IF was a major pathway, constituting 73.0% of the monitored activity. 3. In summary,the intestinal metabolism of IF was demonstrated for the first time and these in vitro data indicate that the intestinal metabolism of IF could contribute significantly to the overall first-pass metabolism.     

Influence of short-term use of dexamethasone on the pharmacokinetics of ifosfamide in patients.

Dexamethasone induces the hepatic cytochrome P450 3A and, therefore, is predicted to change the pharmacokinetics, activities, and side effects of drugs metabolized by cytochrome P450 3A. The aim of this study was to determine whether the pharmacokinetics of the cytochrome P450 3A-dependent oxazaphosphorine cytostatic drug ifosfamide is influenced by short-term antiemetic use of dexamethasone in patients. The peak concentration and area under the curve (AUC) were determined for the parent compound and the metabolites 4-hydroxyifosfamide and chloracetaldehyde in eight patients who received two cycles of ICE chemotherapy (ifosfamide 5 g/m(2) day 1, carboplatin 300 mg/m(2) day 1, etoposide 100 mg/m(2) days 1-3). One cycle included concomitant administration of dexamethasone (40 mg over 30 min, 16 h and 1 h before chemotherapy), whereas the other did not. The half-lives of ifosfamide, 4-hydroxyifosfamide, and chloracetaldehyde were shorter with concomitant administration of dexamethasone, but the differences were not statistically significant. In addition, there were no significant differences in the ifosfamide and active 4-hydroxyifosfamide peak concentrations and AUCs when dexamethasone was included. After dexamethasone administration, the chloracetaldehyde peak concentration was slightly increased by 1.5-fold and the AUC by 1.3-fold; however, these increases were not statistically significant. In conclusion, dexamethasone comedication in ICE chemotherapy did not change the ifosfamide pharmacokinetics. Thus, dexamethasone can be used safely as an antiemetic drug in ifosfamide chemotherapy.     

N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats

BACKGROUND AND PURPOSE: Ifosfamide nephrotoxicity is a serious adverse effect for children undergoing cancer chemotherapy. Our recent in vitro studies have shown that the antioxidant N-acetylcysteine (NAC), which is used extensively as an antidote for paracetamol (acetaminophen) poisoning in children, protects renal tubular cells from ifosfamide-induced toxicity at a clinically relevant concentration. To further validate this observation, an animal model of ifosfamide-induced nephrotoxicity was used to determine the protective effect of NAC. EXPERIMENTAL APPROACH: Male Wistar albino rats were injected intraperitoneally with saline, ifosfamide (50 or 80 mg kg(-1) daily for 5 days), NAC (1.2 g kg(-1) daily for 6 days) or ifosfamide+NAC (for 6 days). Twenty-four hours after the last injection, rats were killed and serum and urine were collected for biochemical analysis. Kidney tissues were obtained for analysis of glutathione, glutathione S-transferase and lipid peroxide levels as well as histology analysis. KEY RESULTS: NAC markedly reduces the severity of renal dysfunction induced by ifosfamide with a significant decrease in elevations of serum creatinine (57.8+/-2.3 vs 45.25+/-2.1 micromol l(-1)) as well as a reduced elevation of beta2-microglobulin excretion (25.44+/-3.3 vs 8.83+/-1.3 nmol l(-1)) and magnesium excretion (19.5+/-1.5 vs 11.16+/-1.5 mmol l(-1)). Moreover, NAC significantly improved the ifosfamide-induced glutathione depletion and the decrease of glutathione S-transferase activity, lowered the elevation of lipid peroxides and prevented typical morphological damages in renal tubules and glomeruli. CONCLUSIONS AND IMPLICATIONS: Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.     

Population pharmacokinetic-pharmacodynamic modeling of TF-505 using extension of indirect response model by incorporating a circadian rhythm in healthy volunteers

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the newly developed drug, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), was characterized via a population approach in early human study. Healthy volunteers were divided into six groups. The groups received four single doses (25, 50, 75 or 100 mg) and 2 multiple doses (12.5 or 25 mg) of TF-505, respectively. Dihydrotestosterone (DHT) data were collected to assess TF-505 pharmacodynamics. Population PK/PD modeling of TF-505 was performed via mixed-effects modeling using the NONMEM software package. The final PK-PD model incorporates a two-compartment PK model and an extended indirect PD model. The population PK parameters were 0.197 h(-1) for the k(a), 0.0678 h(-1) for k(e), 12.5 l for V(c), 0.0645 h(-1) for k(12), 0.0723 h(-1) for k(21). Extension of indirect response model by incorporating a time-dependent periodic function for k(in) takes into account the chronopharmacologic rhythms (I(max): 0.706+/-0.297, IC(50): 1.01+/-1.64 (microg/ml), k(out): 0.221+/-0.0486 (h(-1)), R(m): 20.4+/-8.08 (% h(-1)), R(amp): 5.06+/-3.43 (% h(-1)), T(z): 5.01+/-0.407 (h) (Population mean+/-S.E.)). R(m) is the mean DHT synthesis rate, R(amp) is the amplitude of the DHT synthesis rate, and T(z) is the acrophase time, signifying maximum synthesis rate. The present study represents a successful population PK-PD model using the full data from early human studies. The population parameters thus obtained could provide useful indicators for the determination of dosage regimens in exploratory studies in patient populations.     

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.0 micrograms ml-1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1-acid glycoprotein (AGP). 2. Smokers and non-smokers exhibited similar half-lives (6.48 +/- 1.49 vs 6.66 +/- 1.02 h), apparent total body clearances (0.100 +/- 0.020 vs 0.117 +/- 0.034 l h-1 kg-1), mean renal clearances (0.043 +/- 0.0093 vs 0.057 +/- 0.013 l h-1 kg-1) and apparent intrinsic metabolic clearances (0.057 +/- 0.015 vs 0.060 +/- 0.024 l h-1 kg-1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non-smokers resulted in an increase in the AUC of the active metabolite N-despropyl disopyramide (MND), but not significantly (3.8 +/- 1.6 vs 4.1 +/- 2.3 micrograms ml-1 h). Similar results were observed in smokers (3.5 +/- 1.4 vs 3.9 +/- 2.0 micrograms ml-1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non-smokers was significantly decreased upon phenobarbitone treatment (43 +/- 6% vs 25 +/- 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/- 6% vs 31 +/- 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/- 19.9 mg dl-1 vs 68.0 +/- 40.7 mg dl-1) or smokers (64.5 +/- 15.7 vs 67.9 +/- 14.9). Similarly, when AGP concentration was estimated in serum from non-smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/- 1.3 vs 47.9 +/- 16.8 mg dl-1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.     

Population pharmacokinetics and pharmacodynamics of mitomycin during intraoperative hyperthermic intraperitoneal chemotherapy

BACKGROUND: During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies. OBJECTIVE: To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC. METHODS: Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity. RESULTS: Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model. CONCLUSIONS: The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPEC.     

Time- and concentration-dependent induction of CYP1A1 and CYP1A2 in precision-cut rat liver slices incubated in dynamic organ culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin

In a previous 24-h study, precision-cut rat liver slices were validated as a useful in vitro model for assessing the dose-related induction of CYP1A1 and CYP1A2 in rat liver following exposure to 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Further assessment of the utility of this model was accomplished by initially exposing rat liver slices to medium containing TCDD (0.01 nM) for 24 h and incubating the slices up to an additional 72 h in TCDD-free medium. The slices remained viable throughout the incubation period with an intracellular potassium content varying from 45.2 +/- 2.3 micromol/g at 48 h to 50.0 +/- 1.6 micromol/g at 72 h. In TCDD-exposed slices, CYP1A1 protein and its respective enzymatic activity, the O-deethylation of ethoxyresorufin (EROD), significantly increased with time over the 96-h incubation period, with EROD activity increasing from 63.6 +/- 14.2 at 24 h to 905 +/- 291 pmol/mg/min at 96 h. Under identical incubation conditions, but in the absence of TCDD, the EROD activity for the control liver slices ranged from 14. 3 +/- 4.3 to 44.9 +/- 11.9 pmol/min/mg. Conversely, the level of CYP1A2 protein and its respective activity (acetanilide hydroxylation) transiently decreased from 24 to 96 h with no significant differences observed between the control (0 nM TCDD) and treatment group (0.01 nM TCDD). The concentration-effect relationship at 96 h was characterized by incubating rat liver slices for the initial 24 h in medium containing TCDD at concentrations ranging from 0.1 pM to 10 nM. Induction of CYP1A1 protein and EROD activity was observed for all treatment groups with the 10 nM TCDD treatment group displaying greater than 100-fold induction compared to control (0 nM TCDD). Immunohistochemical localization of CYP1A1 protein within liver slices supported the time- and concentration-dependent induction of EROD activity by TCDD. The induction of CYP1A1 was initially observed to be centrilobular, with increased expression due to both elevated CYP1A1 within cells and the recruitment of additional cells expressing CYP1A1 throughout the entire liver slice. Additionally, the immunohistochemical analysis of the liver slices demonstrated the conservation of tissue architecture following up to 96 h of incubation in dynamic organ culture and provided further evidence for maintenance of tissue viability. In comparison to CYP1A1, the induction of CYP1A2 at 96 h was a less sensitive response, with significant induction of CYP1A2 protein and its respective activity occurring at a medium concentration of 0.1 nM TCDD (686 pg/g liver). In general, increasing the incubation period from 24 to 96 h markedly increased TCDD-induced expression of CYP1A1 and minimally enhanced CYP1A2 expression. Moreover, extending the incubation period to 96 h resulted in in vitro induction profiles for CYP1A1 and CYP1A2 that were qualitatively and quantitatively similar to that previously observed following in vivo exposure to TCDD (Drahushuk et al., Toxicol. Appl. Pharmacol. 140, 393-403, 1996).     

Metabolism of enantiomers of the cytostatic ifosfamide

3H-labelled enantiomers of the cytostatic drug ifosfamide isolated by chromatographic resolution, were intraperitoneally applied to female NMRI mice. The concentrations of ifosfamide and its metabolites in blood and urine were determined. Both enantiomers of ifosfamide are eliminated at almost equal rates. The metabolites with anticancer activity are formed to a greater extent, 4-ketoifosfamide is formed stereoselectively from S(-)-ifosfamide. In vivo the conversion of aldo- to 4-hydroxyifosfamide does not take place.     

Population pharmacokinetics of raltitrexed in patients with advanced solid tumours

AIMS: To investigate the population pharmacokinetics of raltitrexed in patients with advanced solid tumours and to identify patient covariates contributing to the interpatient variability in the pharmacokinetics of raltitrexed. METHODS: Patient covariate and concentration-time data were collected from patients receiving 0.1-4.5 mg m(-2) raltitrexed during the early clinical trials of raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate population mean estimates for clearance (CL) and central volume of distribution (V). The relationship between individual estimates of the pharmacokinetic parameters and patient covariates was examined and the influence of significant covariates on the population parameter estimates and their variance was investigated using stepwise multiple linear regression. The performance of the developed model was tested using an independent validation dataset. All patient data were pooled in the total cohort to refine the population pharmacokinetic model for raltitrexed. RESULTS: three-compartment pharmacokinetic model was used to fit the concentration-time data of raltitrexed. Estimated creatinine clearance (CL(CR)) was found to influence significantly the CL of raltitrexed and explained 35% of variability in this parameter, whilst body weight (WT) and serum albumin concentrations (ALB) accounted for 56% of the variability in V. Satisfactory prediction (mean prediction error 0.17 micro g l(-1) and root mean square prediction error 4.99 micro g l(-1)) of the observed raltitrexed concentrations was obtained in the model validation step. The final population mean estimates were 2.17 l h(-1)[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI 6.02, 6.70) for CL and V, respectively. Interpatient variability in the pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential covariates were included in the final model. The following covariate relationships with raltitrexed parameters were described by the final population model: CL (l h(-1)) = 0.54 + 0.02 CL(CR) (ml min(-1)) and V (l) = 6.64 + 0.08 WT (kg) - 0.16 ALB (g l(-1)). CONCLUSIONS: A population pharmacokinetic model has been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic parameters of raltitrexed are markedly influenced by the patient's renal function, body weight and serum albumin levels, which may be taken into account in dose individualization. The use of influential covariates to guide anticancer dosage selection may result in less variability in drug exposure and potentially a better clinical outcome.     

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.     

Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain

The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships. A composite model consisting of an E(max) model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the concentration-effect relationship. For both compounds, a full anti-hyperalgesic effect was observed. The values of the EC50 for the anti-hyperalgesic effect were (mean+/-S.D.): 3170+/-1460 and 2660+/-1200 ng/ml for MCPA and 2'dCPA versus 178+/-51 ng/ml for the reference full agonist 5'deoxyribose-N6-cyclopentyl-adenosine (5'dCPA). The values of the slope for the anti-nociceptive effect were 1.9+/-0.30 and 1.2+/-0.20 g.microl/ng, respectively, versus 55+/-8 g microl/ng for 5'dCPA. Adenosine A1 receptor partial agonists behave as full agonists with regard to the anti-hyperalgesic effect in neuropathic pain, but the anti-nociceptive effect is diminished.     

Application of pharmacokinetic-pharmacodynamic modelling for the comparison of quinazoline alpha-adrenoceptor agonists in normotensive volunteers

Prazosin, doxazosin, and trimazosin are structural analogues with relatively selective peripheral alpha 1-adrenoceptor antagonist properties. The relationships between the pharmacokinetics and pharmacodynamics for these three drugs have been studied following acute intravenous administration in normotensive subjects. The mean terminal elimination half-life (+/- SD) for prazosin was 2.0 +/- 0.4 h, and that for trimazosin was comparable at 3.1 +/- 0.3 h, whilst the mean terminal elimination half-life for doxazosin was significantly longer at 9.4 +/- 1.5 h. The clearance of prazosin (mean, 327 +/- 78 ml/min) was greater than that of both doxazosin (139 +/- 30 ml/min) and trimazosin (67 +/- 29 ml/min). The hypotensive effects of prazosin and doxazosin were fitted to an integrated pharmacokinetic-pharmacodynamic model with similar resulting values for the parameter describing responsiveness. The pharmacodynamic profile of trimazosin was subjected to similar analysis and was most appropriately fitted to a model incorporating an effect compartment associated with both parent drug and its major metabolite 1-hydroxy trimazosin.     

Pharmacokinetic and pharmacodynamic population modeling of orally administered rabeprazole in healthy Chinese volunteers by the NONMEM method.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the proton pump inhibitor rabeprazole in healthy Chinese volunteers was characterized via a population approach. Healthy Chinese male volunteers were enrolled in the clinical trial. Subjects were divided into three groups by their CYP2C19 genotype. Serum concentrations of rabeprazole were determined using high performance liquid chromatography (HPLC). The intragastric pH values were monitored simultaneously. Data analysis was performed using nonlinear mixed-effects modeling as implemented in the NONMEM software package. The final PK-PD model incorporated a one-compartment PK model with one-order absorption from the gastroenteric trace, first-order elimination pathway with one fixed-effect genotype modeling, and a full sigmoidal Emax PD model (X +/- SE: E0 = 2.30 +/- 0.189; Emax = 7.32 +/- 0.662; EC50 = 51.3 +/- 2.142 ng/ml; Hill coefficient = 5.00 +/- 0.556). The time profiles for concentration and pH value, as well as the concentration-pH value relationship of rabeprazole in healthy Chinese volunteers were well described by the developed population PK-PD model.     

Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice.

The hepatotoxicity of acetaminophen is conventionally ascribed to metabolism by CYP450 to N-acetyl-p-benzoquinone imine and covalent binding to proteins. We investigated a potential role for oxidative stress by determining the effect of the ferric chelator deferoxamine (Desferal) on acetaminophen (paracetamol)-induced hepatotoxicity in mice. Administration of deferoxamine (75 mg/kg) 1 h after a toxic dose of acetaminophen (300 mg/kg) significantly delayed the development of the toxicity without altering covalent binding. In saline-treated mice serum ALT was 18 +/- 2 IU/l. In acetaminophen-treated mice serum alanine aminotransferase (ALT) was 779 +/- 271 at 2 h, 7421 +/- 552 IU/l at 4 h, 5732 +/- 523 IU/l at 8 h, and 5984 +/- 497 IU/l at 24 h. In acetaminophen plus deferoxamine-treated mice, serum ALT was 80 +/- 10 at 2 h, 472 +/- 74 IU/l at 4 h, 2149 +/- 597 IU/l at 8 h, and 5766 +/- 388 at 24 h. Deferoxamine at 1 h after acetaminophen did not decrease serum ALT at 12 h; however, deferoxamine at 1 and 4 h, or deferoxamine at 1 h plus N-acetylcysteine at 4 h to replete hepatic glutathione, decreased the toxicity from 5625 +/- 310 IU/l to 3436 +/- 546 IU/l and 3003 +/- 282 IU/l, respectively. Deferoxamine plus N-acetylcysteine at 1.25 h after acetaminophen was more effective at decreasing the 24 h toxicity than N-acetylcysteine alone. In acetaminophen treated mice, higher doses of deferoxamine (150-300 mg/kg) at 1 h greatly increased the observed hepatotoxicity at 4 h in a dose responsive manner, but deferoxamine alone was nontoxic.     

Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients

AIM: To study the possible influence of patient characteristics on abacavir pharmacokinetics. METHODS: A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM. RESULTS: Abacavir pharmacokinetics was well described by a two-compartment open model with linear absorption and elimination. Typical population estimates for the absorption rate constant (Ka), the apparent central distribution volume (Vc/F), the apparent peripheral distribution volume (Vp/F), the apparent intercompartmental clearance (Q/F) and the apparent plasma clearance (CL/F) were 1.8 h(-1), 75 l, 23.6 l, 10 l h(-1) and 47.5 l h(-1), respectively. Apparent plasma clearance was positively related to bodyweight. Individual Bayesian estimates of CL/F were used to calculate abacavir AUC. The latter decreased from 10.7 +/- 5.0 to 5.7 +/- 1.6 mgh l(-1) when bodyweight increased from 36 to 102 kg. This drop in abacavir exposure could lead to suboptimal treatment for the heaviest patients, as antiviral efficacy of abacavir is known to be related to its AUC. A 400 mg abacavir dose would be necessary to achieve adequate exposure to abacavir in patients weighing more than 60 kg. CONCLUSIONS: The apparent plasma clearance of abacavir was positively related to bodyweight. The efficacy of the current recommended abacavir dosage for patients with high bodyweight should be evaluated in further studies.     

Aspects of chronic oral treatment with thyrotropin-releasing hormone: the hypothalamic-pituitary-thyroid axis in rats. A study with a pharmacological dose of thyrotropin-releasing hormone.

The effects of 16 days of oral treatment with thyrotropin-releasing hormone (TRH, 1 mg/24 h) on serum levels of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) and the kinetics of TRH in the blood were studied in normal rats. A second group of animals served as controls. TRH was dissolved by sonification (10 mg/l) and was stable in tap water. TRH was measured by a radioimmunoassay procedure (normal range: 20-80 pmol/l, antiserum K2B9 1:120,000 final dilution). An increase in basal TSH (7,200 +/- 440 ng/l, mean +/- SD) was found after 2 days of treatment (11,420 +/- 810 ng/l), but a significant increase was observed after 5 days of treatment (12,530 +/- 640 ng/l, p less than 0.001). T4 serum concentrations remained in the normal range during the entire period of study, whereas T3 serum concentrations (0.76 +/- 0.1 micrograms/l) were increased to 1.22 +/- 0.2 micrograms/l on day 5 (p less than 0.001). A subsequent decline of TSH, T4 and T3 up to the end of the study was observed. TRHmax concentrations were registered on day 5 (790 +/- 24 pmol/l). The mean value of TRHmax was 723 +/- 34 pmol/l. To improve the stability of TRH in tap water, 1-ml samples of drinking water with dissolved TRH were measured. The mean TRH concentration in drinking water was 73 +/- 1.5% (SD). No significant correlations were found between the area under the curve of TSH (184,340 ng.l-1.24 h) and that of TRH (14,954 pmol.l-1.24 h).(ABSTRACT TRUNCATED AT 250 WORDS)