Assessment of Maraviroc Exposure-Response Relationship at 48 Weeks in Treatment-Experienced HIV-1-Infected Patients in the MOTIVATE Studies.

Efficacy exposure-response relationships of the CCR5 antagonist maraviroc were evaluated across two phase III clinical trials. This post-hoc analysis used 48-week efficacy data from 841 treatment-experienced patients infected with CCR5-tropic human immunodeficiency virus type 1 (HIV-1), identified by the enhanced sensitivity Trofile assay. Probability of treatment success (viral RNA <50 copies/ml) was modeled using generalized additive logistic regression, testing exposure, clinical, and virologic variables. Prognostic factors for treatment success (in decreasing order of Akaike information criterion (AIC) change) were: maraviroc treatment, high-weighted overall susceptibility to background treatment, absence of an undetectable maraviroc concentration, high baseline CD4 count (BCD4), low viral load (VL), race (other than black), absence of non-R5 baseline tropism (BTRP), and absence of fosamprenavir (FPV). No concentration-response relationship was found with treatment (maraviroc vs. placebo) and presence/absence of undetectable maraviroc concentration (adherence marker) in the model. The maraviroc doses studied (300 or 150 mg with potent CYP3A4 inhibitors once (q.d.)/twice daily (b.i.d.)) deliver concentrations near the top of the concentration-response curve.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e64; doi:10.1038/psp.2013.42; published online 14 August 2013.

Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Nonlinearity detection: advantages of nonlinear mixed-effects modeling.

The purpose of this study was to address the question of whether the use of nonlinear mixed-effect models has an impact on the detection and characterization of nonlinear processes (pharmacokinetic and pharmacodynamic) in rich data obtained from a few subjects. Simulations were used to assess the difference between applying population analysis, ie, nonlinear mixed-effects models as implemented in NONMEM, and the standard 2-stage (STS) method as the data analysis method for detection and characterization of nonlinearities. Three situations were considered, 2 pharmacokinetic and 1 pharmacodynamic. Both the first-order (FO) and FO conditional estimation (FOCE) algorithms were used for the population analyses. Within each situation, rich data were simulated for 8 subjects at multiple dose levels. The true nonlinear model and a simpler linear model were fit to each data set using each of the STS, FO, and FOCE methods. Criteria were prespecified to determine when each data analysis method detected the true nonlinear model. For all 3 simulated situations, the application of population analysis with the FOCE algorithm enabled the detection and characterization of the true nonlinear models in at least a 4-fold lower dose level than the STS approach. For both of the pharmacokinetic settings, population analysis with the FO algorithm performed much more poorly than the STS approach. The superior detection and characterization of nonlinearities provided by population analysis with the FOCE algorithm should allow drug developers to better predict and define how a drug should be used in clinical practice in such situations.

Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients.

Deriving a population pharmacokinetic model from real data is always associated with numerous assumptions. Violations of these assumptions, especially if undetected, may lead to inappropriate conclusions being made from the analysis. Routinely, only a few of the assumptions are explicitly stated and justified in the reporting of a population model. Here, we attempt to be exhaustive in the presentation of the assumptions made in the course of an analysis of moxonidine pharmacokinetics. The different ways that assumptions were justified, through experience, graphical examination, or additional modeling, are outlined. Models for relaxing assumptions regarding the covariate and statistical submodels, not previously reported in the area of population pharmacokinetic modeling, are also described.

The population pharmacokinetics of recombinant- and urinary-human follicle stimulating hormone in women.

AIMS: To characterize the pharmacokinetics of recombinant-human follicle stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvolution techniques. METHODS: Sparse data were available from 62 female patients who received u-hFSH intramuscularly (i.m.) and 60 female patients who received r-hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF-ET) procedure. The dose of u-hFSH and r-hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u-hFSH/r-hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r-hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash-out. The volunteers then received multiple r-hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u-hFSH, 150 IU, given by the i.v. and i.m. routes. RESULTS: Analysis of the intensively sampled r-hFSH and u-hFSH data sets found that disposition could be described using a two-compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 and 18 h, respectively. The different bioavailabilities (F) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r-hFSH and u-hFSH data. The population estimates of apparent clearance (CL/F) were 0.71 and 0.33 l h(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 l h(-1) at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r-hFSH and u-hFSH were essentially the same, 26% and 25%, respectively. CONCLUSIONS: The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.

Discrimination between rival dosing histories.

PURPOSE: In population pharmacokinetic studies, the dosing history is sometimes recorded in more than one way. The purpose of this study was to develop and evaluate a procedure for discriminating between rival dosing histories, i.e., for each individual in a data set, identify the dosing history that is the most plausible. METHODS: The procedure consists of four steps. In the first step we identify individuals whose dosing histories produce predictions that are consistent. In the second step these individuals are used to build a population pharmacokinetic model which is used, in step three, to select the dosing history for the individuals not identified in step one. In step four the population model is refined using the best available dosing histories for all individuals. The proposed procedure was evaluated using both simulations and a real data set, in which two dosing histories, based on patient diaries and electronic monitoring devices (MEMS) were available. RESULTS: In the real data set, estimated variabilities were almost always lower when the selected dosing histories were used compared to when no selection procedure was used. The diary dosing histories were selected more often than the MEMS dosing histories. In the simulations, the parameter estimates obtained using the selection procedure were closer to the true parameter values compared to when only one of the dosing histories was used. CONCLUSIONS: The proposed procedure appears to be robust and should be beneficial in at least two respects: improved parameter estimation of population pharmacokinetic and PK/PD models and objective information by which dosage recording methodologies can be compared and patient dose recording behavior can be assessed.

A population model for the follicular growth in women treated with follicle stimulating hormone.

PURPOSE: To develop a pharmacodynamic model that can describe the time course of follicular growth and to investigate the influence, if any, of covariates on the parameters of the model. METHODS: A population pharmacodynamic analysis was performed on total follicular volume data obtained after in vitro fertilisation and embryo transfer with urinary or recombinant human follicle stimulating hormone (FSH) treatment. A growth model in which the increase in total follicular volume with time is a function of several possible components was chosen. RESULTS: In the final population pharmacodynamic model, increase in total follicular volume (TFV) was described by the equation: dTFV/dt = Emax.TFV/(TFV + TFV50) + constant, in which Emax, TFV50, and constant were 508 mm3/hr (interindividual variability 72%), 12,900 mm3 (66%), and 1.43 mm3/hr (91%), respectively. Growth was positively correlated to baseline estradiol levels, so that Emax and TFV50 changed 0.52% for every picomolar change from the median baseline estradiol value of 100 pmol/L. Growth was negatively correlated to pretreatment FSH levels, so that individuals with a median FSH (6.7 IU/L) were expected to have a fivefold higher total follicular volume at day 10 after the start of treatment, compared to individuals at the high end of the pretreatment FSH range (12 IU/L). No relationship between FSH concentration and follicular growth was found. The urinary versus recombinant origin of the drug did not influence the ovarian response. CONCLUSION: Women with high endogenous levels of FSH respond less to standard doses of exogenous FSH. Women with higher baseline levels of estradiol have larger expected follicular growth rates.

Comparison of some practical sampling strategies for population pharmacokinetic studies.

Using population analysis, sparsely sampled Phase 3 clinical data can be utilized to determine the pharmacokinetic characteristics of the target population. Data arising from such studies are likely to be constrained to certain sampling windows, i.e., the visiting hours at the study clinic. When the sampling window is narrow compared to the half-life of the drug, the advantage of taking more than one sample is not obvious. Study designs with one or two samples per visit have been compared with respect to (i) precision and bias of the population parameter estimates, (ii) the ability to identify the underlying pharmacokinetic model, and (iii) the estimation of individual parameter values. The first point was assessed using simulated data while the latter two were studied using a real data set. Results show: (i) Parameter estimates are more biased and imprecise when only one sample is taken compared to when two samples are obtained, this is true irrespective of the time span between the two samples. (ii) Ability to identify a more complex model is increased if two samples are taken. Specifically, the variability between occasions can be quantified. (iii) Two-sample designs are generally better with respect to prediction of individual parameter values. Even minor changes to commonly employed study designs, in this case the addition of one sample at each study occasion, can improve quality and quantity of the information obtained.

Felodipine population dose-response and concentration-response relationships in patients with essential hypertension.

OBJECTIVES: To characterize the population dose-response and concentration-response relationships of felodipine and to investigate the influence of patient variables on these relationships. METHODS: We studied 239 evaluable patients with mild to moderate essential hypertension in a multicenter, randomized, double-blind dose-escalation trial, followed by an optional open-label maintenance phase for the remainder of 1 year. Extended-release felodipine (2.5 to 20 mg) monotherapy was given once daily. Felodipine plasma concentration and sitting diastolic blood pressure were measured at approximately 2 and 24 hours after drug administration. Analysis, performed with use of the population approach (NONMEM program), accounted for baseline and placebo effects. RESULTS: A saturation (Emax) model best described both felodipine dose response (only 24-hour postdose data) and concentration response. The maximum effect (Emax) characterizing dose response was found to increase linearly with age and was estimated to be 20.6 mm Hg in the typical individual (60 years of age). The dose at which 50% of the maximum effect is achieved (D50) was estimated to be 11.1 mg. The Emax characterizing concentration response also increased linearly with age and was estimated to be 27.8 mm Hg for the typical individual. The concentration at which 50% of the maximum effect is achieved (C50) was related to plasma renin activity (PRA) by the following: (21.6.PRA)/(0.25 + PRA) nmol/L; its value in the typical individual was estimated to be about 16.9 nmol/L. Felodipine (oral) clearance decreased with increasing age, up to 60 years, and was larger in black patients. CONCLUSIONS: The effects of age on felodipine pharmacokinetics and pharmacodynamics lead to a heightened antihypertensive response in the elderly. A starting dose of 2.5 mg daily is recommended, especially in elderly patients.

Interaction between structural, statistical, and covariate models in population pharmacokinetic analysis.

The influence of the choice of pharmacokinetic model on subsequent determination of covariate relationships in population pharmacokinetic analysis was studied using both simulated and real data sets. Simulations and data analysis were both performed with the program NONMEM. Data were simulated using a two-compartment model, but at late sample times, so that preferential selection of the two-compartment model should have been impossible. A simple categorical covariate acting on clearance was included. Initially, on the basis of a difference in the objective function values, the two-compartment model was selected over the one-compartment model. Only when the complexity of the one-compartment model was increased in terms of the covariate and statistical models was the difference in objective function values of the two structural models negligible. For two real data sets, with which the two-compartment model was not selected preferentially, more complex covariate relationships were supported with the one-compartment model than with the two-compartment model. Thus, the choice of structural model can be affected as much by the covariate model as can the choice of covariate model be affected by the structural model; the two choices are interestingly intertwined. A suggestion on how to proceed when building population pharmacokinetic models is given.

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.

A novel statistical approach for the comparison of analytical methods to measure angiotensin converting enzyme activity, enalaprilat, and benazeprilat.

Two different analytical techniques were used to measure angiotensin converting enzyme (ACE) activity, and three different methods were used to measure each of the ACE inhibitors enalaprilat and benazeprilat. All measurements were made in human plasma. The groups of methods were compared by two different statistical approaches. First, the means of the methods were compared by the paired t test or analysis of variance, depending on whether two or three different methods were under comparison. Second, the squared coefficients of variation of the methods were compared by the Jackknife technique. The dual statistical approach employed enabled both the accuracy and the variability of the analytical methods to be compared and is a superior approach to the inappropriate use of correlation coefficients that are commonly used to compare analytical techniques. No statistically significant difference was found between the two assays used to measure ACE activity. Differences were found between the three methods to measure enalaprilat, although no obvious reason could be found for this phenomenon. Significant differences were also found between the three methods used to measure benazeprilat and were attributed to the presence of metabolites interfering in the nonspecific assay methods.

Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis.

A prospective simulation study has been carried out to evaluate the effect of potential misspecification of the absorption rate constant (ka) in population pharmacokinetic analysis when few to no concentration-time data were available in the absorption phase and estimation of ka was not possible. Data were simulated for 100 subjects using a one-compartment model at steady state with first-order input. Data were generated over a range of ka values: ka was misspecified in the NONMEM analysis by factors of 0.25, 0.5, 1, 2, 3, and 4. In general, clearance (CL) was typically estimated with a small, constant underprediction, regardless of the range of misspecification of ka or whether data were present in the absorption phase. The same was not true for volume of distribution (V), values were biased and sensitive to the degree of misspecification, but only when the data contained even a little information about absorption. If studies are to be designed in which information absorption is either not required or is of no therapeutic use, then blood samples could be concentrated in the postabsorption phase and the absorption input fixed according to the best a priori information available.

The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.

1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.

Variability in the pharmacokinetics of epirubicin: a population analysis.

Population pharmacokinetic analysis of the anticancer agent epirubicin was carried out using the program NONMEM. Data were available from 36 patients aged 20-73 years, of whom 23 were women. All subjects exhibited normal liver and renal function. Epirubicin was given as a short-term i.v. infusion over the dose range of 25-100 mg/m2, and an average of 11 plasma samples/subject were taken for a period of up to 72 h after each dose. A Two compartment model was fitted to the data, characterised by the parameters clearance, volume of the central compartment, alpha and beta. Clearance was tested as a linear function of various demographic and/or biochemical features. A significant proportion of the variability in clearance could be attributed to sex, and also to age in women. For example, a 25-year-old man would display an average clearance of 95 l/h, whereas a 70-year-old woman would exhibit an average clearance of 64 l/h. Such differences in clearance might be important in the selection of epirubicin dose regimens.