Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided.
A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.
The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.
Biological Products , Humans , Administration, Intravenous
BACKGROUND AND OBJECTIVE: We aimed to quantify the daratumumab concentration- and CD38 dynamics-dependent pharmacokinetics using a pharmacodynamic mediated disposition model (PDMDD) in patients with multiple myeloma (MMY) following daratumumab IV or SC monotherapy. Daratumumab, a human IgG monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, has been approved to treat patients with multiple myeloma (MM). METHODS: In total, 7788 daratumumab plasma samples from 850 patients with diagnosis of MMY were used. The serum concentration-time data of daratumumab were analysed using nonlinear mixed-effects modeling with NONMEM®. The PDMDD with quasi steady-state approximation (QSS) was compared to the previously developed Michaelis-Menten (MM) approximation with respect to the parameter estimates, the goodness-of-fit plots and prediction-corrected visual predictive check, as well as model-based simulations. The effect of patients' covariates on daratumumab pharmacokinetics was also investigated. RESULTS: The QSS approximation characterized the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics within the doses ranging from 0.1 to 24 mg/kg after IV administration and 1200 and 1800 mg after SC administration in patients with MMY, mechanistically describing the binding of daratumumab and CD38, the internalization of the daratumumab-CD38 complex and the CD38 turnover. Compared to the previously developed MM approximation, the MM approximation with the non-constant total target and dose-correction provided substantial improvement of the model fit, but it was still not as good as the QSS approximation. The effect of the previously identified covariates as well as the newly identified covariate (baseline M protein) on daratumumab pharmacokinetics was confirmed, but the magnitude of the effect was deemed not clinically relevant. CONCLUSIONS: Accounting for the CD38 turnover and its binding capacity to daratumumab, the QSS approximation provided a mechanistic interpretation of daratumumab PK parameters and consequently well described the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics. CLINICAL STUDIES INCLUDED IN THE ANALYSIS WERE REGISTERED WITH THE NCT NUMBER BELOW AT HTTP://WWW. CLINICALTRIALS: GOV : MMY1002 (ClinicalTrials.gov: NCT02116569), MMY1003 (NCT02852837), MMY1004 (NCT02519452), MMY1008 (NCT03242889), GEN501 (NCT00574288), MMY2002 (NCT01985126), MMY3012 (NCT03277105).
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Antibodies, Monoclonal/adverse effects
AIM: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure-response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). METHODS: The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. RESULTS: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration-time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK-efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. CONCLUSIONS: The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.
Multiple Myeloma , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Treatment Outcome
JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.v. or 1, 3 and 10 mg/kg s.c. Plasma and liver concentrations were analyzed simultaneously using nonlinear mixed-effects modeling with the NONMEM 7.4. A population PK model consisting of a two-compartment disposition model with transporter-mediated drug disposition, including internalization to the liver compartment, linear elimination from plasma and liver, and first-order absorption following subcutaneous administration, was suitable to describe both plasma and liver PK. After subcutaneous dosing, absolute bioavailability was complete and flip-flop kinetics were observed. JNJ-73763989 distributes from plasma to liver via transporter-mediated liver internalization in less than 24 hours, with sustained (>42 days) liver exposure. The saturation of transporter-mediated liver internalization was hypothesized to be due to asialoglycoprotein receptor saturation. Increasing the dose decreased the relative liver uptake efficiency in mice for intravenously and, to a lesser extent, subcutaneously administered JNJ-73763989. Lower dose levels administered subcutaneously in mice can maximize the proportion of the dose reaching the liver. SIGNIFICANCE STATEMENT: Pharmacokinetic modeling of JNJ-73763989 liver and plasma concentration-time data in mice indicated that the proportion of JNJ-73763989 reaching the liver may be increased by administering lower subcutaneous doses compared to higher intravenous doses. Model-based simulations can be applied to optimize the dose and regimen combination.
Hepatitis B, Chronic , Acetylgalactosamine , Animals , Asialoglycoprotein Receptor , Dependovirus/genetics , Hepatitis B virus , Male , Mice , RNA, Messenger , RNA, Small Interfering
BACKGROUND: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. METHODS: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. RESULTS: Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46-0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67-0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02-1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. CONCLUSIONS: The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib's therapeutic benefit/risk ratio. CLINICAL TRIAL REGISTRATION NUMBER: NCT02365597.
Carcinoma, Transitional Cell/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Quinoxalines/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Aged , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Quinoxalines/adverse effects , Receptors, Fibroblast Growth Factor/metabolism , Survival Rate
A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.
Neoplasms , Pyrazoles , Female , Humans , Neoplasms/drug therapy , Phosphates/therapeutic use , Pyrazoles/pharmacokinetics , Quinoxalines/pharmacokinetics
BACKGROUND: Macitentan and its active metabolite, aprocitentan, are non-peptide, potent, dual endothelin receptor antagonists. Macitentan is approved for the treatment of pulmonary arterial hypertension in adults, at a dose of 10 mg/day. OBJECTIVE: The objective of this study was to develop a comprehensive population model to describe the pharmacokinetics of macitentan and aprocitentan in healthy adults and adult subjects with pulmonary arterial hypertension. METHODS: Pharmacokinetic data of 452 subjects in nine studies, after single and repeated doses (dose range 0.2-600 mg), were pooled for a non-linear mixed-effects analysis and the assessment of covariates, i.e., body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters. RESULTS: The final model was an open one-compartment disposition model, with linear elimination for macitentan and linear formation and elimination for aprocitentan. A semi-mechanistic absorption model described the dose dependency and multiple peaks observed for macitentan. For a female patient with pulmonary arterial hypertension after oral administration at 10 mg, macitentan reached a maximum concentration after 9 h and, following daily dosing, reached steady state after 3 days with a twofold accumulation factor. The apparent volume of distribution was 34 L and clearance was 1.39 L/h. Aprocitentan reached maximum concentration after 51 h and steady state after 9 days, with a 12.5-fold accumulation factor. Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters. CONCLUSIONS: The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations. Several covariates significantly influenced the pharmacokinetics of macitentan and aprocitentan, but none was considered clinically relevant.
Pulmonary Arterial Hypertension , Adult , Female , Healthy Volunteers , Humans , Pyrimidines , Sulfonamides
A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1 -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.
Neoplasms/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Quinoxalines/administration & dosage , Quinoxalines/pharmacokinetics , Administration, Oral , Adult , Aged , Biological Availability , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Computer Simulation , Drug Administration Schedule , Female , Healthy Volunteers , Humans , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Neoplasms/drug therapy , Protein Kinase Inhibitors/blood , Pyrazoles/blood , Quinoxalines/blood
PURPOSE: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. METHODS: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. RESULTS: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval. CONCLUSIONS: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.
Drug Resistance, Neoplasm/drug effects , Heart Rate/drug effects , Heart/drug effects , Neoplasms/drug therapy , Pyrazoles/administration & dosage , Quinoxalines/administration & dosage , Adult , Aged , Aged, 80 and over , Electrocardiography , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasms/pathology , Patient Safety , Prognosis , Pyrazoles/pharmacokinetics , Quinoxalines/pharmacokinetics , Tissue Distribution , Young Adult
Quantifying the uncertainty around endpoints used for decision-making in drug development is essential. In nonlinear mixed-effects models (NLMEM) analysis, this uncertainty is derived from the uncertainty around model parameters. Different methods to assess parameter uncertainty exist, but scrutiny towards their adequacy is low. In a previous publication, sampling importance resampling (SIR) was proposed as a fast and assumption-light method for the estimation of parameter uncertainty. A non-iterative implementation of SIR proved adequate for a set of simple NLMEM, but the choice of SIR settings remained an issue. This issue was alleviated in the present work through the development of an automated, iterative SIR procedure. The new procedure was tested on 25 real data examples covering a wide range of pharmacokinetic and pharmacodynamic NLMEM featuring continuous and categorical endpoints, with up to 39 estimated parameters and varying data richness. SIR led to appropriate results after 3 iterations on average. SIR was also compared with the covariance matrix, bootstrap and stochastic simulations and estimations (SSE). SIR was about 10 times faster than the bootstrap. SIR led to relative standard errors similar to the covariance matrix and SSE. SIR parameter 95% confidence intervals also displayed similar asymmetry to SSE. In conclusion, the automated SIR procedure was successfully applied over a large variety of cases, and its user-friendly implementation in the PsN program enables an efficient estimation of parameter uncertainty in NLMEM.
Drug Discovery/statistics & numerical data , Models, Statistical , Nonlinear Dynamics , Uncertainty
Knowledge of the uncertainty in model parameters is essential for decision-making in drug development. Contrarily to other aspects of nonlinear mixed effects models (NLMEM), scrutiny towards assumptions around parameter uncertainty is low, and no diagnostic exists to judge whether the estimated uncertainty is appropriate. This work aims at introducing a diagnostic capable of assessing the appropriateness of a given parameter uncertainty distribution. The new diagnostic was applied to case bootstrap examples in order to investigate for which dataset sizes case bootstrap is appropriate for NLMEM. The proposed diagnostic is a plot comparing the distribution of differences in objective function values (dOFV) of the proposed uncertainty distribution to a theoretical Chi square distribution with degrees of freedom equal to the number of estimated model parameters. The uncertainty distribution was deemed appropriate if its dOFV distribution was overlaid with or below the theoretical distribution. The diagnostic was applied to the bootstrap of two real data and two simulated data examples, featuring pharmacokinetic and pharmacodynamic models and datasets of 20-200 individuals with between 2 and 5 observations on average per individual. In the real data examples, the diagnostic indicated that case bootstrap was unsuitable for NLMEM analyses with around 70 individuals. A measure of parameter-specific "effective" sample size was proposed as a potentially better indicator of bootstrap adequacy than overall sample size. In the simulation examples, bootstrap confidence intervals were shown to underestimate inter-individual variability at low sample sizes. The proposed diagnostic proved a relevant tool for assessing the appropriateness of a given parameter uncertainty distribution and as such it should be routinely used.
Drug Discovery/statistics & numerical data , Models, Statistical , Nonlinear Dynamics , Pefloxacin/pharmacokinetics , Phenobarbital/pharmacokinetics , Uncertainty , Computer Simulation , Humans , Models, Biological , Pefloxacin/administration & dosage , Phenobarbital/administration & dosage
Taking parameter uncertainty into account is key to make drug development decisions such as testing whether trial endpoints meet defined criteria. Currently used methods for assessing parameter uncertainty in NLMEM have limitations, and there is a lack of diagnostics for when these limitations occur. In this work, a method based on sampling importance resampling (SIR) is proposed, which has the advantage of being free of distributional assumptions and does not require repeated parameter estimation. To perform SIR, a high number of parameter vectors are simulated from a given proposal uncertainty distribution. Their likelihood given the true uncertainty is then approximated by the ratio between the likelihood of the data given each vector and the likelihood of each vector given the proposal distribution, called the importance ratio. Non-parametric uncertainty distributions are obtained by resampling parameter vectors according to probabilities proportional to their importance ratios. Two simulation examples and three real data examples were used to define how SIR should be performed with NLMEM and to investigate the performance of the method. The simulation examples showed that SIR was able to recover the true parameter uncertainty. The real data examples showed that parameter 95 % confidence intervals (CI) obtained with SIR, the covariance matrix, bootstrap and log-likelihood profiling were generally in agreement when 95 % CI were symmetric. For parameters showing asymmetric 95 % CI, SIR 95 % CI provided a close agreement with log-likelihood profiling but often differed from bootstrap 95 % CI which had been shown to be suboptimal for the chosen examples. This work also provides guidance towards the SIR workflow, i.e.,which proposal distribution to choose and how many parameter vectors to sample when performing SIR, using diagnostics developed for this purpose. SIR is a promising approach for assessing parameter uncertainty as it is applicable in many situations where other methods for assessing parameter uncertainty fail, such as in the presence of small datasets, highly nonlinear models or meta-analysis.
Imidazoles/pharmacokinetics , Models, Biological , Nonlinear Dynamics , Pefloxacin/pharmacokinetics , Phenobarbital/pharmacokinetics , Uncertainty , Administration, Oral , Algorithms , Computer Simulation , Confidence Intervals , Humans , Imidazoles/administration & dosage , Injections, Intravenous , Models, Statistical , Pefloxacin/administration & dosage , Phenobarbital/administration & dosage , Software
Nonlinear mixed effects models parameters are commonly estimated using maximum likelihood. The properties of these estimators depend on the assumption that residual errors are independent and normally distributed with mean zero and correctly defined variance. Violations of this assumption can cause bias in parameter estimates, invalidate the likelihood ratio test and preclude simulation of real-life like data. The choice of error model is mostly done on a case-by-case basis from a limited set of commonly used models. In this work, two strategies are proposed to extend and unify residual error modeling: a dynamic transform-both-sides approach combined with a power error model (dTBS) capable of handling skewed and/or heteroscedastic residuals, and a t-distributed residual error model allowing for symmetric heavy tails. Ten published pharmacokinetic and pharmacodynamic models as well as stochastic simulation and estimation were used to evaluate the two approaches. dTBS always led to significant improvements in objective function value, with most examples displaying some degree of right-skewness and variances proportional to predictions raised to powers between 0 and 1. The t-distribution led to significant improvement for 5 out of 10 models with degrees of freedom between 3 and 9. Six models were most improved by the t-distribution while four models benefited more from dTBS. Changes in other model parameter estimates were observed. In conclusion, the use of dTBS and/or t-distribution models provides a flexible and easy-to-use framework capable of characterizing all commonly encountered residual error distributions.
Computer Simulation , Nonlinear Dynamics , Probability , Pharmacokinetics , Regression Analysis
