Sara E. Rosenbaum

A Population Pharmacokinetic Analysis of Nelfinavir Mesylate in Human Immunodeficiency Virus-Infected Patients Enrolled in a Phase III Clinical Trial

ABSTRACT A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (ka). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F),V/F, and ka were estimated, and model 2, in which V/F and ka were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41.9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.

Population pharmacokinetics of cyclosporine in cardiopulmonary transplant recipients.

A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune™) or a microemulsion (Neoral™). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals [CI] 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 − 11.3 × ITRA + 23.5 × CF + 0.129 × (WT − 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population.

Population Pharmacokinetics of Mycophenolic Acid and Its 2 Glucuronidated Metabolites in Kidney Transplant Recipients

The population pharmacokinetics of mycophenolic acid (MPA) and its phenolic (MPAG) and acyl (AcMPAG) glucuronide metabolites were studied in patients taking enteric‐coated mycophenolate sodium. Plasma samples (n = 232), obtained from 18 renal transplant recipients, were analyzed for MPA, MPAG, and AcMPAG using a validated high‐performance liquid chromatography/ultraviolet assay. Population pharmacokinetic analysis was performed using NONMEM. The pharmacokinetics of MPA were best described by a 2‐compartment model, with MPAG and AcMPAG produced from the central compartment and with enterohepatic recirculation of MPA via these 2 metabolites. Population mean estimates for MPA were apparent clearance (CL/F) of 10.6 L/h (interindividual variability [IIV] = 21.4%) and apparent volume of distribution of the central compartment (V1/F) of 25.9 L (IIV = 87.8%). Mean elimination rate constants of MPAG and AcMPAG were 0.323 h−1 (IIV = 29.1%) and 0.206 h−1 (IIV = 48.8%), respectively. The mean fraction of MPA converted to MPAG and AcMPAG, normalized by their volumes of distribution (FMAG and FMAC, respectively), was also estimated. The elimination rate constant for MPAG and FMAC was influenced by glomerular filtration rate in patients with renal impairment. The visual predictive check, based on 100 simulated data sets each for MPA, MPAG, and AcMPAG, found that the final pharmacokinetic model adequately predicts the observed concentrations of all 3 species.

Development of a Population Pharmacokinetic Model for Atorvastatin Acid and Its Lactone Metabolite

Background and ObjectivesAtorvastatin lactone, a metabolite of the HMG-CoA reductase inhibitor (statin) atorvastatin acid, is believed to be myotoxic. Our objectives were to develop a population pharmacokinetic model for atorvastatin acid and its lactone metabolite and to identify patient characteristics that are predictive of variability in the pharmacokinetic parameters of the parent drug and its lactone metabolite.Subjects and MethodsTwenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10mg once daily for 7 days. Plasma samples taken on day 7 at 0 hours (predose) and 0.5, 1, 1.5, 2, 3, 5, 7, 9, 12, 22 and 24 hours post-dose were analysed for both atorvastatin acid and atorvastatin lactone, using a validated liquid chromatography assay with tandem mass spectrometry, and the data were modelled using nonlinear mixed-effects modelling software (NONMEM®). The influence of the patients’ demographic characteristics, biochemical indices and pharmacogenomics was evaluated. Final model validation was carried out using a visual predictive check.ResultsThe pharmacokinetics of atorvastatin acid and atorvastatin lactone were best described by two- and one-compartment models, respectively. The main pharmacokinetic parameters of atorvastatin acid (mean [relative standard error RSE]) for a subject with mean covariate values were the first-order absorption rate constant (3.5 h−1 fixed); oral clearance (504 L/h [29%]); apparent volume of the central compartment (3250 L [16.5%]); and apparent volume of the peripheral compartment (2170 L [9.3%]). The main pharmacokinetic parameters of atorvastatin lactone (mean [RSE]) were the apparent clearance to atorvastatin acid (24 L/h [154%]); apparent total body clearance (116L/h [9.5%]); and apparent volume of distribution (137L [33.7%]). The value of aspartate transaminase was identified as a significant covariate for the apparent volume of the central compartment for atorvastatin acid and for the apparent total body clearance of atorvastatin lactone, signifying the importance of liver function in atorvastatin pharmacokinetics. The visual predictive plots demonstrated that the model adequately described the pharmacokinetics of both species.ConclusionA population pharmacokinetics model was developed and validated to describe atorvastatin acid and its lactone metabolite concentration-time data. This model may be useful for atorvastatin dose individualization or analysis of sparse data.

Population Pharmacokinetics: Fundamentals, Methods and Applications

AbstractThe application of pharmacokinetic principles can maximize the goals of drug administration from the time a drug is first administered to man during the initial phases of development, to well beyond the approval of the NDA. Population pharmacokinetics is playing an increasing role in this regard. This paper provides a comprehensive review of the principles and methods of population pharmacokinetics. Finally, examples of how population pharmacokinetics may be applied to optimize drug administration are presented.

Effect of variability in hepatic clearance on the bioequivalence parameters of a drug and its metabolite: simulations using a pharmacostatistical model

A semi-physiological pharmacostatistical model was developed and used to study the manner in which intra-individual variability in hepatic clearance is transmitted to the area-under the plasma concentration-time curve from zero to infinity (AUC) of a drug and its metabolite. In order to clarify the effects, the model contained no other sources of variability. As the drugs hepatic extraction ratio increased, the coefficient of variation (CV) of the AUC of the drug increased, whereas that of the metabolite decreased. The AUC of the metabolite increased as the drugs non-hepatic clearance increased. At high extraction ratios, the CV of the AUC of the drug was insensitive to the contributions of other forms of clearance. The results suggest that under certain circumstances, smaller samples sizes could be used in bioequivalence studies for highly variable drugs if the test were based on the metabolite rather than the parent drug.

The Application of Population Pharmacokinetics to the Drug Development Process

Population pharmacokinetics is playing an increasing role in clinical drug development. An overview of the population approach, including software and the advantages and limitations of the approach compared to the traditional approach to pharmacokinetic studies, is given. This paper also documents how the area has evolved over the past 15 years and addresses some of the issues that have arisen over the design and conduct of population studies. Finally, some alternative applications of the population approach are given for areas other than clinical drug development.

Bioequivalence Parameters of Parent Drug and Its First-Pass Metabolite: Comparative Sensitivity to Sources of Pharmacokinetic Variability

AbstractThe relative susceptibilities of a drug and its first-pass metabolite to various forms of pharmacokinetic variability were studied. Plasma concentrations of both species were simulated under conditions of interindividual variability in intrinsic hepatic clearance, intraindividual variability in hepatic clearance, and/or a concentration-dependent model for assay error. In comparison to the metabolite, the plasma concentrations of the parent drug displayed a heightened sensitivity to all forms of error. The bioequivalence parameters, AUC, Cmax, and Tmax of the parent drug and the metabolite were determined from an abbreviated data set. Compared to the metabolite, the AUC and Cmax of the parent drug were much more sensitive to the added variability. The Tmax of both species displayed similar variability. For a given level of manufacturer risk, a much larger group of subjects would be necessary to demonstrate bioequivalence with respect to the drug than with respect to the metabolite.

Dse and Limitations of the Truncated Area Under the Curve in Bioequivalence Testing

AbstractComputer simulations were used to evaluate the truncated area under the plasma level-time curves (AUC.) as indicators of the bioequivalence between test and reference products. Plasma concentrations were simulated from one and two compartment open models using first order absorption rate constants (Ka) and bioavailability (F) ranging respectively from 45 to 200% and 60 to 140% of the reference values. The pharmacokinetic parameters were selected to cover a wide range of disposition rate constants (0.01-0.79 hr.−1). The area under the blood level-time curves was calculated using the trapezoidal rule at each time point (t) according to a conventional sampling regimen. The extent of absorption (AUC.inf) was calculated, using integrals of the general blood equations. The ratios of AUC.: test to reference and AUCL to AUC.were determined. For most simulations, the ratios changed very little between the end of the absorption period, the last time point and the time infinity. AUC, was not a good parameter...

Interventions to Increase Physician Participation in a Voluntary Reporting System: The Rhode Island Adverse Drug Reaction Reporting Project

AbstractThe voluntary reporting system for adverse drug reactions, operated by the US Food and Drug Administration (FDA), is an important component of the postmarketing surveillance process. Despite this, the system is under-used by the physicians upon whom it depends. The FDA contracted with the Rhode Island Department of Health in 1985 to conduct a pilot reporting project to investigate how physician participation in the voluntary reporting system could be increased. A variety of different educational interventions were directed at the Rhode Island physician community. By the end of a two year study period, reports had increased 17-fold. Evaluation of the interventions through a survey of Rhode Island physicians indicated that hospital presentations, a project newsletter and mailings were the most effective educational interventions. Conversely, journal articles, advertisements and articles in hospital newsletters were identified as the least effective interventions. This assessment of project intervent...