The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep.

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.

Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis.

BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

AIMS: Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. METHODS: The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. RESULTS: About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. CONCLUSION: We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.

Evaluation of bootstrap methods for estimating uncertainty of parameters in nonlinear mixed-effects models: a simulation study in population pharmacokinetics.

Bootstrap methods are used in many disciplines to estimate the uncertainty of parameters, including multi-level or linear mixed-effects models. Residual-based bootstrap methods which resample both random effects and residuals are an alternative approach to case bootstrap, which resamples the individuals. Most PKPD applications use the case bootstrap, for which software is available. In this study, we evaluated the performance of three bootstrap methods (case bootstrap, nonparametric residual bootstrap and parametric bootstrap) by a simulation study and compared them to that of an asymptotic method (Asym) in estimating uncertainty of parameters in nonlinear mixed-effects models (NLMEM) with heteroscedastic error. This simulation was conducted using as an example of the PK model for aflibercept, an anti-angiogenic drug. As expected, we found that the bootstrap methods provided better estimates of uncertainty for parameters in NLMEM with high nonlinearity and having balanced designs compared to the Asym, as implemented in MONOLIX. Overall, the parametric bootstrap performed better than the case bootstrap as the true model and variance distribution were used. However, the case bootstrap is faster and simpler as it makes no assumptions on the model and preserves both between subject and residual variability in one resampling step. The performance of the nonparametric residual bootstrap was found to be limited when applying to NLMEM due to its failure to reflate the variance before resampling in unbalanced designs where the Asym and the parametric bootstrap performed well and better than case bootstrap even with stratification.

The population pharmacokinetics of allopurinol and oxypurinol in patients with gout.

PURPOSE: The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics. METHODS: Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent-metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling. RESULTS: Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively. CONCLUSIONS: The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.

A comparison of bootstrap approaches for estimating uncertainty of parameters in linear mixed-effects models.

A version of the nonparametric bootstrap, which resamples the entire subjects from original data, called the case bootstrap, has been increasingly used for estimating uncertainty of parameters in mixed-effects models. It is usually applied to obtain more robust estimates of the parameters and more realistic confidence intervals (CIs). Alternative bootstrap methods, such as residual bootstrap and parametric bootstrap that resample both random effects and residuals, have been proposed to better take into account the hierarchical structure of multi-level and longitudinal data. However, few studies have been performed to compare these different approaches. In this study, we used simulation to evaluate bootstrap methods proposed for linear mixed-effect models. We also compared the results obtained by maximum likelihood (ML) and restricted maximum likelihood (REML). Our simulation studies evidenced the good performance of the case bootstrap as well as the bootstraps of both random effects and residuals. On the other hand, the bootstrap methods that resample only the residuals and the bootstraps combining case and residuals performed poorly. REML and ML provided similar bootstrap estimates of uncertainty, but there was slightly more bias and poorer coverage rate for variance parameters with ML in the sparse design. We applied the proposed methods to a real dataset from a study investigating the natural evolution of Parkinson's disease and were able to confirm that the methods provide plausible estimates of uncertainty. Given that most real-life datasets tend to exhibit heterogeneity in sampling schedules, the residual bootstraps would be expected to perform better than the case bootstrap.

Progression of motor and nonmotor features of Parkinson's disease and their response to treatment.

AIMS: (i) To describe the progression of the cardinal features of Parkinson's disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease-modifying effects of anti-parkinsonian treatments. METHODS: Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features [tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD)] were derived from the total unified Parkinson's disease rating scale (total UPDRS), cognitive status from the mini-mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM-D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters. RESULTS: Tremor progressed more slowly (half-time of 3.9 years) than all other motor features (half-time 2-3 years). The MMSE progression was negligible, while HAM-D progressed with a half-time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED50 of 1237 mg day⁻¹ compared with 7-24 mg day⁻¹ for other motor and nonmotor features). Other anti-parkinsonian treatments had much smaller symptomatic effects. All treatments had disease-modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression. CONCLUSIONS: This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti-parkinsonian treatments have symptomatic and disease-modifying effects on all major features of PD.

Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson's disease.

AIM: To describe the time to clinical events (death, disability, cognitive impairment and depression) in Parkinson's disease using the time course of disease status and treatment as explanatory variables. METHODS: Disease status based on the Unified Parkinson's Disease Rating Scale (UPDRS) and the time to clinical outcome events were obtained from 800 patients who initially had early Parkinson's disease. Parametric hazard models were used to describe the time to the events of interest. RESULTS: Time course of disease status (severity) was an important predictor of clinical outcome events. There was an increased hazard ratio for death 1.4 (95% CI 1.31, 149), disability 2.75 (95% CI 2.30, 3.28), cognitive impairment 4.35 (95% CI 1.94, 9.74), and depressive state 1.43 (95% CI 1.26, 1.63) with each 10 unit increase of UPDRS. Age at study entry increased the hazard with hazard ratios of 49.1 (95% CI 8.7, 278) for death, 4.76 (95% CI 1.10, 20.6) for disability and 90.0 (95% CI 63.3-128) for cognitive impairment at age 60 years. Selegiline treatment had independent effects as a predictor of death at 8 year follow-up with a hazard ratio of 2.54 (95% CI 1.51, 4.25) but had beneficial effects on disability with a hazard ratio of 0.363 (95% CI 0.132, 0.533) and depression with a hazard ratio of 0.372 (95% CI 0.12, 0.552). CONCLUSIONS: Our findings show that the time course of disease status based on UPDRS is a much better predictor of future clinical events than any baseline disease characteristic. Continued selegiline treatment appears to increase the hazard of death.

Safe and effective variability-a criterion for dose individualization.

BACKGROUND: A primary goal of clinical pharmacology is to understand the factors that determine the dose-effect relationship and to use this knowledge to individualize drug dose. METHODS: A principle-based criterion is proposed for deciding among alternative individualization methods. RESULTS: Safe and effective variability defines the maximum acceptable population variability in drug concentration around the population average. CONCLUSIONS: A decision on whether patient covariates alone are sufficient, or whether therapeutic drug monitoring in combination with target concentration intervention is needed, can be made by comparing the remaining population variability after a particular dosing method with the safe and effective variability.

The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.

PURPOSE: Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV. METHODS: Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks. RESULTS: The patients had a median age of 32 (range 19-55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment. CONCLUSION: Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications.

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

Nonlinear pharmacokinetics of piperacillin in healthy volunteers--implications for optimal dosage regimens.

AIMS: (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens. METHODS: We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4g piperacillin as a single 5min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC >50% of the dosing interval. RESULTS: A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70kg subject we estimated 4.40lh(-1) for nonrenal clearance, 5.70lh(-1) for first-order renal clearance, 170mgh(-1) for V(max) , and 49.7mgl(-1) for K(m) for the mixed-order renal elimination. The BOV was 39% for V(max) , 117% for K(m) , and 8.5% for total clearance. A 30min infusion of 4g every 6h achieved robust (≥90%) PTAs for MICs ≤12mgl(-1) . As an alternative mode of administration, a 5h infusion of 6g every 8h achieved robust PTAs for MICs ≤48mgl(-1) . CONCLUSIONS: Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48mgl(-1) .

A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients.

PURPOSE: This tumor response pharmacodynamic model aims to describe primary lesion shrinkage in non-small cell lung cancer over time and determine if concentration-based exposure metrics for gemcitabine or that of its metabolites, 2',2'-difluorodeoxyuridine or gemcitabine triphosphate, are better than gemcitabine dose for prediction of individual response. EXPERIMENTAL DESIGN: Gemcitabine was given thrice weekly on days 1 and 8 in combination with carboplatin, which was given only on day 1 of every cycle. Gemcitabine amount in the body and area under the concentration-time curves of plasma gemcitabine, 2',2'-difluorodeoxyuridine, and intracellular gemcitabine triphosphate in white cells were compared to determine which best describes tumor shrinkage over time. Tumor growth kinetics were described using a Gompertz-like model. RESULTS: The apparent half-life for the effect of gemcitabine was 7.67 weeks. The tumor turnover time constant was 21.8 week.cm. Baseline tumor size and gemcitabine amount in the body to attain 50% of tumor shrinkage were estimated to be 6.66 cm and 10,600 mg. There was no evidence of relapse during treatment. CONCLUSIONS: Concentration-based exposure metrics for gemcitabine and its metabolites were no better than gemcitabine amount in predicting tumor shrinkage in primary lung cancer lesions. Gemcitabine dose-based models did marginally better than treatment-based models that ignored doses of drug administered to patients. Modeling tumor shrinkage in primary lesions can be used to quantify individual sensitivity and response to antitumor effects of anticancer drugs.

Washout and delayed start designs for identifying disease modifying effects in slowly progressive diseases using disease progression analysis.

Treatment of a slowly progressive disease, such as Parkinson's and Alzheimer's disease should slow down or even reverse progression of the disease. For estimating the actual treatment effect a clinical trial should allow the time course of treatment effects to be distinguished from those due to natural disease progression. A symptomatic treatment effect has a rapid onset, which will disappear after treatment cessation, whereas disease modifying effects are slow and persistent. Our objective was to compare the power of washout and delayed start designs for distinguishing symptomatic and disease modifying effects using disease progression modelling. The effect of dropout due to worsening disease status on the power was also considered.The change in the Unified Parkinson's Disease Rating Scale score over time was simulated, assuming that a treatment has a combined symptomatic and disease modifying effect. The simulated data were then fitted with the combined effect model and also with alternative models with either symptomatic or disease modifying effects alone. The power was derived from the number of times that the true model was correctly distinguished from the alternative models.Including a washout period in which the subjects are followed up after cessation of treatment substantially increases the power to distinguish different treatment effect types (washout>80%; delayed start<60%). Dropout of 40%-50% during the trial has a small effect on power (7% decrease). Under the assumptions of the simulation we found a clear advantage from using the washout design compared with a delayed start design.

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure.

AIMS: The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS: Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS: The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E(max) model with E(max) of -11.7 mmHg and EC(50) of 423 microg l(-1) was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS: AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 microg l(-1), indicating that a loading dose of 200 microg kg(-1) and a maintenance dose of 400 microg kg(-1) h(-1) would be appropriate for the initial treatment of AHF.

Lack of association of single-nucleotide polymorphisms in pregnane X receptor, hepatic nuclear factor 4alpha, and constitutive androstane receptor with docetaxel pharmacokinetics.

PURPOSE: This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4alpha (HNF4alpha), on the pharmacokinetics of docetaxel. EXPERIMENTAL DESIGN: Docetaxel was given as an i.v. infusion of 75 mg/m(2) over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4alpha were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model. RESULTS: Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, alpha1 acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4alpha and 5' untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance. CONCLUSIONS: SNPs identified in CYP3A gene expression regulators CAR, HNF4alpha, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.

Population pharmacokinetics of humanized monoclonal antibody HuCC49deltaCH2 and murine antibody CC49 in colorectal cancer patients.

To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of (125)I-HuCC49deltaCH2 and (125)I-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was used to fit the pharmacokinetic data. Model stability and performance were assessed using a visual predictive check procedure. Different clinical trial designs were evaluated by simulation in combination with Bayesian estimation method to predict the optimal time for surgery. The results showed that HuCC49deltaCH2 had 65% faster clearance from blood circulation and 24% shorter mean residence time than CC49. Population pharmacokinetic analysis identified body weight as the only covariate to explain between-subject variability in clearance, intercompartmental flow rate, and volume of distribution. Model predictions indicated a wide interval for the optimal time of surgery, suggesting that it would be beneficial to individualize the time of surgery for each patient by measurement of antibody disposition. Clinical trial designs with at least 3 measurements of antibody disposition were found to be better than an empirical direct observation method for the optimal prediction of surgery time.

Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors.

OBJECTIVE: Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients. METHODS: Data were pooled from 9 clinical trials. Topotecan, as a single-agent therapy, was administered as a daily 30-minute intravenous infusion for 5 days on a 3-week cycle. Doses of 0.2 to 2.0 mg/m(2) were studied; concentration and neutropenic event data were obtained on multiple occasions. The pharmacokinetics were characterized with use of hierarchical nonlinear regression. The relationship between severity of neutropenia and exposure was characterized with use of logistic regression. RESULTS: The pharmacokinetics of topotecan were described with a linear 2-compartment model. Compromised renal function, low body weight, and poor Eastern Cooperative Oncology Group performance status were determinants of lower clearance, resulting in elevated exposure. Application of covariates reduced interpatient variability in clearance. Logistic regression showed that topotecan area under the concentration-time curve from 0 to 24 hours was predictive of the severity of neutropenia; the only other significant covariate was the number of courses of previous treatment with platinum-based regimens. CONCLUSIONS: Patients with compromised renal function, low body weight, or poor performance status had low topotecan clearance. Patients with high topotecan AUC had an increased probability of experiencing severe neutropenia, which was greater if the patient had been pretreated with platinum-based agents. The use of covariates to individualize dose would result in less variability in exposure, reducing the likelihood of severe neutropenia and potentially improving treatment benefit.