A population pharmacokinetic-pharmacodynamic model evaluating efficacy of nalbuphine extended-release in patients with prurigo nodularis.

AIMS: Population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models were used to describe the exposure-response (E-R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's 'average'; itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-h recall. Simulations based on the model E-R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7-day average of the 24-h WI-NRS by at least 30% from baseline in most of the analysis population. METHODS: Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A maximum effect ( E max ) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). RESULTS: The PK-PD model predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of E max , respectively. Exposures associated with 80% of E max were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID. CONCLUSION: Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

Usability of a novel digital medicine system in adults with schizophrenia treated with sensor-embedded tablets of aripiprazole.

OBJECTIVE: Digital medicine system (DMS) is a novel drug-device combination that objectively measures and reports medication ingestion. The DMS consists of medication embedded with an ingestible sensor (digital medicine), a wearable sensor, and software applications. This study evaluated usability of the DMS in adults with schizophrenia rated by both patients and their health care providers (HCPs) during 8-week treatment with prescribed doses of digital aripiprazole. METHODS: Six US sites enrolled outpatients into this Phase IIa, open-label study (NCT02219009). The study comprised a screening phase, a training phase (three weekly site visits), and a 5-week independent phase. Patients and HCPs independently rated usability of and satisfaction with the DMS. RESULTS: Sixty-seven patients were enrolled, and 49 (73.1%) patients completed the study. The mean age (SD) of the patients was 46.6 years (9.7 years); the majority of them were male (74.6%), black (76.1%), and rated mildly ill on the Clinical Global Impression - Severity scale (70.1%). By the end of week 8 or early termination, 82.1% (55/67) of patients had replaced the wearable sensor independently or with minimal assistance, based on HCP rating. The patients used the wearable sensor for a mean (SD) of 70.7% (24.7%) and a median of 77.8% of their time in the trial. The patients contacted a call center most frequently at week 1. At the last visit, 78% (47/60) of patients were somewhat satisfied/satisfied/extremely satisfied with the DMS. CONCLUSION: A high proportion of patients with schizophrenia were able to use the DMS and reported satisfaction with the DMS. These data support the potential utility of the DMS in clinical practice.

Optimization of a Digital Medicine System in Psychiatry.

BACKGROUND: Nonadherence to medication compromises the effectiveness of psychiatric treatments in patients with serious mental illness (SMI). A newly developed digital medicine system (DMS) offers an opportunity to objectively assess and report patient medication adherence. DMS includes a wearable sensor that receives a data signal from a medication tablet with an embedded ingestible sensor after ingestion of the medication and transmits that data to the patient's mobile device to display health care information for the patient and treatment team. METHODS/RESULTS: Development of a DMS requires a program that investigates safety, tolerability, and usability of the system in patients with SMI. It necessitates rapid design adaptation of the individual components and the integrated system and human factors studies with the intended users. This article describes the program's methodology and shows results from 3 early studies, conducted in 2013 and 2014, to illustrate diversity of the programs' methodology. First, a standard 28-day study showed minimal skin irritation and demonstrated acceptable wearability of the wearable sensor. Second, a 16-week study provided usability feedback from patients with SMI and caregivers to improve the mobile application. Third, end-to-end bench-level integrated system testing led to multiple substudies of a master protocol (ClinicalTrials.gov identifier: NCT02091882) to investigate various aspects of the system (eg, ingestible sensor detection and latency). CONCLUSIONS: To develop a DMS in psychiatry, the system's multiple components must be considered simultaneously using various methodologies. A focus on usability, along with agile evaluation and feedback across studies, provides an optimal strategy for ensuring patient acceptance and successful regulatory review.

Developing a Digital Medicine System in Psychiatry: Ingestion Detection Rate and Latency Period.

BACKGROUND: A digital medicine system (DMS) has been developed to measure and report adherence to an atypical antipsychotic, aripiprazole, in psychiatric patients. The DMS consists of 3 components: ingestible sensor embedded in a medication tablet, wearable sensor, and secure mobile and cloud-based applications. An umbrella study protocol was designed to rapidly assess the technical performance and safety of the DMS in multiple substudies to guide the technology development. METHODS: Two sequential substudies enrolled 30 and 29 healthy volunteers between March-April 2014 and February-March 2015, respectively, to assess detection accuracy of the ingestible sensor by the DMS and the latency period between ingestion and detection of the ingestion by the wearable sensor or the cloud-based server. RESULTS: The first substudy identified areas for improvement using early versions of the wearable sensor and the mobile application. The second substudy tested updated versions of the components and showed an overall ingestion detection rate of 96.6%. Mean latency times for the signal transmission were 1.1-1.3 minutes (from ingestion to the wearable sensor detection) and 6.2-10.3 minutes (from the wearable sensor detection to the server detection). Half of transmissions were completed in < 2 minutes, and ~90% of ingestions were registered by the smartphone within 30 minutes of ingestion. No serious adverse events, discontinuations, or clinically significant laboratory/vital signs findings were reported. CONCLUSIONS: The DMS implementing modified versions of the smartphone application and the wearable sensor has the technical capability to detect and report tablet ingestion with high accuracy and acceptable latency time. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02091882.

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times.

Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse sampling conditions when the dosing interval is less than the terminal half-life of the compound, and the underlying kinetics are monoexponential. Additional effects due to noncompliance with dosing events are not explored and it is assumed that the structural model and reasonable initial estimates of the model parameters are known. Under the conditions of our simulations, with structural model CV % ranging from ~20 to 60 %, parameter estimation inaccuracy derived from error in reported dosing times was largely controlled around 10 % on average. Given that no observed dosing was included in the design and sparse sampling was utilized, we believe these error results represent a practical ceiling given the variability and parameter estimates for the one-compartment model. The findings suggest additional investigations may be of interest and are noteworthy given the inability of current PK software platforms to accommodate error in dosing times.

Development and application of an aggregate adherence metric derived from population pharmacokinetics to inform clinical trial enrichment.

Nonadherence to prescribed medication is a common barrier to effective treatment, and current options to determine adherence are limited. This study describes development of an aggregate adherence measure based on population pharmacokinetics (PK), and its comparison to a subjective questionnaire, the Morisky 8-item medication adherence scale (MMAS8), in a trial of psychiatric patients on stable doses of oral aripiprazole. A comprehensive model was first built using plasma drug concentration data from 24 clinical studies comprising 448 patients with over 13,500 observations. Application of this model to independent patient profiles for a given drug-dosing regimen were used to generate the primary aggregate adherence metric, a ratio of observed versus expected plasma exposures at steady-state. Although the metric is capable of comparing relative adherence across groups, simulations showed that the metric is not sufficiently sensitive as an individual diagnostic in all cases. There were no trends observed between results from calculated aggregate adherence metrics and total scores from MMAS8 in a single-visit clinical trial of 47 patients with bipolar 1 disorder or schizophrenia who were on stable doses of aripiprazole, although a strong association was observed for one MMAS8 question. The range of the metric calculated for patients was between 0.16 and 3.15. The described approach of a novel "reverse" application of population PK to quantify relative adherence with an aggregate measure may be influential for both clinical and pharmacometric communities.

Model-Supported Development of CS-8635: A Fixed-Dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide.

CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. The Phase III study evaluated CS-8635 BP lowering effects only at the highest dose strength among the five dose strengths to be developed. Post-trial M&S was performed using an integrated dataset from three Phase III programs; CS-8635 plus two prior dual combinations. M&S robustly estimated and described the BP lowering effects of CS-8635 evaluated in a clinical setting. Furthermore, M&S evaluated BP lowering effects of the additional four dose strengths not studied. In summary, M&S aided the development of the clinical study and full characterization of the BP lowering effects of CS-8635 across intermediate doses.

Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery.

Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

Pharmacokinetics of olmesartan medoxomil in pediatric patients with hypertension.

BACKGROUND: The prevalence and importance of hypertension in younger patients is becoming increasingly recognized; however, only a limited number of clinical trials have been conducted in the pediatric population. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and short-term safety of olmesartan medoxomil in children and adolescents with hypertension. METHODS: An open-label, multicenter, single-dose study was conducted in children and adolescents aged 12 months-16 years who were receiving treatment for hypertension or, if not currently treated for hypertension, had either a systolic blood pressure (SBP) or diastolic blood pressure (DBP).≥95th percentile, or SBP or DBP ≥90th percentile if diabetic or with a family history of hypertension. Patients were stratified by age: 12-23 months (Group 1; none enrolled), 2-5 years (Group 2; n = 4), 6-12 years (Group 3; n = 10), and 13-16 years (Group 4; n = 10). All patients received a single oral dose of olmesartan medoxomil based on the individual's age and bodyweight. Patients aged <6 years received an oral suspension of olmesartan medoxomil at a dose of 0.3 mg/kg of bodyweight (not to exceed 20 mg), those aged ≥6 years who weighed ≥35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. RESULTS: In Groups 2, 3, and 4, the weight-adjusted apparent total body clearance (CL/F) of olmesartan medoxomil was 0.100 ± 0.034, 0.062 ± 0.020, and 0.072 ± 0.022 L/h/kg, respectively, and the weight-adjusted apparent volume of distribution (Vd/F) was 0.32 ± 0.16, 0.33 ± 0.14, and 0.49 ± 0.23 L/kg, respectively. CL/F and Vd/F in Groups 3 and 4 were not significantly different. Statistical comparisons between Groups 3 or 4 and Group 2 were not performed due to the small sample size of Group 2 (n = 4). Plasma elimination half-life and time to maximum plasma concentration were similar across the three groups. In Groups 3 and 4, considerable interindividual variability was seen in maximum plasma concentration (C(max)), area under the curve (AUC) from time zero to the last measurable concentration, and apparent clearance, with AUC and C(max) approximately 30% greater in Group 3. Four of 24 (16.7%) patients experienced treatment-emergent adverse events that were all mild in severity and considered not drug-related. No deaths, serious adverse events, or discontinuations due to adverse events occurred in the study. CONCLUSIONS: Olmesartan medoxomil was well tolerated and demonstrated a pharmacokinetic profile in pediatric patients similar to that of adults when adjusted for body size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00151814

Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.

Population pharmacokinetic model for a novel oral hypoglycemic formed in vivo: comparing the use of active metabolite data alone versus using data of upstream and downstream metabolites.

The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria. The dataset included 6 phase I and IIa studies in patients with type 2 diabetes mellitus. The pharmacokinetic profile of CS-917 and its metabolites was described by a series of linked 1- and 2-compartmental models. Simulations showed that moderate renal impairment has a clinically significant impact on exposure to R-125338. A separate population pharmacokinetic analysis of R-125338 alone revealed similar results. In conclusion, a population pharmacokinetic model fit to the active moiety alone yielded similar predictions and substantially reduced the analysis time compared to the more complex model developed for CS-917 and its metabolites. Increased exposure to R-125338 in the presence of moderate renal impairment may be an important consideration for dose selection.

Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine 1-phosphate receptor-1 modulator.

CS-0777 is a selective sphingosine 1-phosphate receptor-1 (S1P(1)) modulator under development for treatment of autoimmune conditions. A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS-0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS-0777 resulted in a pronounced, dose-dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for placebo and 0.1, 0.3, 1.0, and 2.5 mg, respectively). Dose-related decreases of similar magnitude were observed for T and B cell subsets. Mean total white blood cell and neutrophil counts remained within normal ranges for all dose levels. CS-0777 was well tolerated, and there were no serious or severe adverse events. Mild, asymptomatic bradycardia and transaminase elevations (<3-fold upper limit of normal), similar to findings for other S1P receptor modulators, were observed at the highest dose level (2.5 mg). Therefore, CS-0777 shows potent activity in humans and may hold potential for treatment of autoimmune conditions such as multiple sclerosis.

Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy.

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras-AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras-AM exposure was associated with a higher incidence of non-CABG-related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non-CABG-related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent.

An integrated analysis of pharmacokinetic (PK) parameter estimates for prasugrel, from 16 phase I clinical pharmacology studies, consolidated exposure estimates from 506 healthy male and female participants and evaluated the effect of specific intrinsic and extrinsic factors on exposure to prasugrel's active metabolite (AM, R-138727). A linear mixed effect model was fitted with study and subject nested within study as random effects and subject factors as fixed effects. Prasugrel AM exposure was similar in males and females, in participants <65 years and ≥65 years, in smokers and nonsmokers, in drinkers and nondrinkers of alcohol, and in Asians, Caucasians, and participants of African and Hispanic descent. Prasugrel AM exposure increased as body weight decreased and was 40% higher in participants <60 kg than in participants ≥60 kg. Exposure in Asians was 40% higher than that in Caucasians, but this difference could be explained by the lower overall weight of the Asian participants and a disproportionately large difference between ethnic groups in lighter participants, especially those <60 kg. These results characterize prasugrel's PK across a range of studies and highlight body weight as the most influential covariate on prasugrel AM exposure, with implications for prasugrel maintenance dosing in clinical practice.

Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.

The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation (AF). In this 12-week, parallel-group, multicentre, multinational study, 1,146 patients with AF and risk of stroke were randomised to edoxaban 30 mg qd, 30 mg bid, 60 mg qd, or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0-3.0. The study was double-blind to edoxaban dose, but open-label to warfarin. Primary outcomes were occurrence of major and/or clinically relevant non-major bleeding and elevated hepatic enzymes and/or bilirubin. Mean age was 65 +/- 8.7 years and 64.4% were warfarin-naïve. Whereas major plus clinically relevant non-major bleeding occurred in 3.2% of patients randomised to warfarin, the incidence of bleeding was significantly higher with the edoxaban 60 mg bid (10.6%; p=0.002) and 30 mg bid regimens (7.8%; p=0.029), but not with the edoxaban 60 mg qd (3.8%) or 30 mg qd regimens (3.0%). For the same total daily dose of 60 mg, both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group. There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups. The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin. In contrast, the edoxaban bid regimens were associated with more bleeding than warfarin. These results suggest that in this three-month study, edoxaban 30 or 60 mg qd are safe and well-tolerated.

Correlation of inhibition of platelet aggregation with cardiovascular and bleeding outcomes in acute coronary syndromes.

Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein 2b/3a (GP2b/3a) antagonists and thienopyridines. IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixed-effects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulations were conducted to evaluate the relationship between IPA and the likelihood of observing a CV event in a 6-month end point trial. Data from 81918 subjects in 20 studies were extracted from the literature. To achieve a 20% relative reduction in CV events would require a further 77% (56%-100%) absolute increase in IPA for IV GP2b/3a antagonists or a further 27%(20%-41%) absolute increase for thienopyridines. CV risk reduction was less in studies with older subjects and greater in studies with greater percentages of male subjects. Assuming a 3% major bleeding rate in the control group, these drugs had a 1% increase in absolute risk as absolute platelet inhibition increases by 60% (range, 40%-80%). This relationship in intrinsic bleeding may be different in different population subtypes. Assuming a 12% event rate, a 6-month active-controlled thienopyridine trial with 3000 subjects could detect a relationship between CV events and IPA with 80% likelihood. Target IPA increases in ACS are an absolute increase of 80% for IV GP2b/3a antagonists and 30% for thienopyridines. Quantitative models using literature data on IPA and CV events can be used to select dose regimens in early stages of drug development.

Quantitative structure-property relationships modeling to predict in vitro and in vivo binding of drugs to the bile sequestrant, colesevelam (Welchol).

Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.

Is a thorough QTc study necessary? The role of modeling and simulation in evaluating the QTc prolongation potential of drugs.

Concentration-QT (C-QT) modeling has been conducted for multiple compounds at various stages of development in different therapeutic areas. Data from available single and multiple ascending-dose (SAD/MAD) studies were pooled to construct population C-QT models, with post hoc predictions of concentration from a pharmacokinetic model. All SAD and MAD studies employed a customized robust QTc assessment with time-matched triplicate electrocardiograms and centralized manual QTc reading. Sources of variability were characterized, and the relationship between covariates and model parameters was explored, with a particular emphasis on correction for heart rate and diurnal variation. The results of population prediction of QTc prolongation were compared to available thorough QTc (TQT) study results, and the C-QT model was evaluated to determine whether it could establish the QTc prolongation relationship without the TQT results. Negative TQT study results confirmed negative simulation results from phase I/II C-QT models. Simulations were undertaken to characterize the ability of pooled C-QT modeling to obviate the need for a TQT. C-QT modeling should be implemented as a standard part of modeling and simulation at different phases of drug development and used in conjunction with other data that influence the need and/or the timing of a TQT study.

Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects.

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 muM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.

Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38.

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras-AM exposures was assessed. The PK of Pras-AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras-AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16-1.45) higher than exposure in patients > or =60 kg. Mean Pras-AM exposures for patients > or =75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.