Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term.

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 µg followed by 50 µg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography-tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one-compartment nonlinear clearance model. The absorption rate constant (ka ) was dependent on both route and dose of administration: buccal 25 µg 0.724 (95% confidence interval, 0.54-0.92) h-1 ; 50 µg 0.531 (0.37-0.63) h-1 ; vaginal 25 µg 0.507 (0. 2-1. 4) h-1 ; and 50 µg 0.246 (0.103-0.453) h-1 . Relative bioavailability for vaginal compared to buccal route was 2.4 (1.63-4.77). There was no effect of body mass index or age on apparent clearance 705 (431-1099) L/h or apparent volume of distribution 632 (343-1008) L. The area under the concentration-time curve to 4 h following the first 25 µg dose of misoprostol was 16.5 (15.4-17.5) pg h/ml for buccal and 34.3 (32.5-36.1) pg h/ml for vaginal administration. The rate of buccal absorption was two times faster than that of vaginal, whereas bioavailability of vaginal administration was 2.4 times higher than that of buccal. Decreased time to delivery observed with vaginal dosing may be due to higher exposure to misoprostol acid compared to buccal.

Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children.

Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes. Additionally, the R and S enantiomers of methadone have unique PK and pharmacodynamic properties. This study aims to describe the PKs of R and S methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in pediatric surgical patients and to identify sources of inter- and intra-individual variability. Children aged 8-17.9 years undergoing orthopedic surgeries received intravenous methadone 0.1 mg/kg intra-operatively followed by oral methadone 0.1 mg/kg postoperatively every 12 h. Pharmacokinetics of R and S methadone and EDDP were determined using liquid chromatography tandem mass spectrometry assays and the data were modeled using nonlinear mixed-effects modeling in NONMEM. R and S methadone PKs were well-described by two-compartment disposition models with first-order absorption and elimination. EDDP metabolites were described by one compartment disposition models with first order elimination. Clearance of both R and S methadone were allometrically scaled by bodyweight. CYP2B6 phenotype was a determinant of the clearance of both the enantiomers in an additive gene model. The intronic CYP3A4 single-nucleotide polymorphism (SNP) rs2246709 was associated with decreased clearance of R and S methadone. Concentrations of AAG and the SNP of AAG rs17650 independently increased the volume of distribution of both the enantiomers. The knowledge of these important covariates will aid in the optimal dosing of methadone in children.

Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model.

AIM: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT2c ) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modelling to identify a plausible drug mechanism of action. MATERIALS AND METHODS: This phase 1, single-centre, double-blind, randomized, placebo-controlled, four-period, two-alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27-39 kg/m2 ). Postprandial TG response (total TG, chylomicrons and very low-density lipoprotein particles [VLDL]-V6) following a high-fat meal were assessed for 11 h postmeal for each dose level. The PK profile was assessed for 96 h postdose. Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using non-linear mixed-effect modelling. RESULTS: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6. CONCLUSIONS: LY significantly reduced the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5-HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a semi-physiological lipokinetic model enabled identification of a plausible drug mechanism of action of LY.

Exposure-Response Modeling to Characterize the Relationship Between Ixekizumab Serum Drug Concentrations and Efficacy Responses at Week 12 in Patients With Moderate to Severe Plaque Psoriasis.

Ixekizumab, a high-affinity monoclonal antibody, selectively targets interleukin-17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed. Separate logistic regression models describing the relationship between ixekizumab concentrations and sPGA or PASI scores at week 12 were used to determine the probability of patients achieving a response and to investigate the impact of various patient factors other than drug concentrations on response rates. Both dosing regimens were efficacious, with higher rates of response achieved with the higher range of observed ixekizumab concentrations after every-2-week dosing. Although higher bodyweight, palmoplantar involvement, lower baseline disease state, or high baseline C-reactive protein were associated with slightly lower response rates, the magnitude of effect of these factors on sPGA(0,1) response was small, with all subgroups able to achieve high levels of response. Other factors tested had no effect including age, sex, and antidrug antibody status. Logistic regression modeling of ixekizumab concentration and efficacy data accurately identified the proportion of responders using sPGA or PASI end points. The higher concentration ranges achieved with 80 mg every 2 weeks versus every 4 weeks were associated with higher response levels.

Semi-physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high-fat meal.

AIMS: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach. METHODS: Healthy individuals from three body mass index population categories: lean (18.5-24.9 kg/m2 ), obese (30-33 kg/m2 ), and very obese (34-40 kg/m2 ) were enrolled in a clinical study to assess the TG response after a high-fat meal, containing 60% fat. Non-linear mixed-effect modelling was used to analyse the TG concentrations of chylomicrons and large VLDL-V6 particles. RESULTS: The TGs in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response; only the VLDL-V6 showed a difference across the populations. A turn-over model successfully described the TG concentration-time profiles of both chylomicrons and large VLDL-V6 particles after the high-fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TGs in the blood, and one compartment each for the chylomicrons and large VLDL-V6 particles. The rate constants for the production of chylomicrons and elimination of large VLDL-V6 particles, along with the conversion rate of chylomicrons to large VLDL-V6 particles were well defined. CONCLUSIONS: This is the first lipokinetic model to describe the absorption of TGs from dietary fats into the blood stream and compares the dynamics of TGs in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.

Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM®. RESULTS: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

Population pharmacokinetic meta-analysis of ramucirumab in cancer patients.

AIMS: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach. METHODS: A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg-1 every 2 weeks or 10 mg kg-1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics. RESULTS: The pharmacokinetics of ramucirumab were well characterized by a two-compartment model. Mean population estimates of clearance, volume of distribution and half-life for a typical 68-kg patient were 0.0148 l h-1 , 5.30 l and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; clearance and central compartment volume increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population. CONCLUSIONS: The final model adequately described the concentration-time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight-normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.

Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer.

Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)-efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure-safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure-efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure-response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215-22. ©2017 AACR.

Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials.

BACKGROUND AND OBJECTIVE: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. METHODS: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. RESULTS: Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree. CONCLUSION: The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.

Dose selection using a semi-mechanistic integrated glucose-insulin-glucagon model: designing phase 2 trials for a novel oral glucokinase activator.

Selecting dosing regimens for phase 2 studies for a novel glucokinase activator LY2599506 is challenging due to the difficulty in modeling and assessing hypoglycemia risk. A semi-mechanistic integrated glucose-insulin-glucagon (GIG) model was developed in NONMEM based on pharmacokinetic, glucose, insulin, glucagon, and meal data obtained from a multiple ascending dose study in patients with Type 2 diabetes mellitus treated with LY2599506 for up to 26 days. The series of differential equations from the NONMEM model was translated into an R script to prospectively predict 24-h glucose profiles following LY2599506 treatment for 3 months for a variety of doses and dosing regimens. The reduction in hemoglobin A1c (HbA1c) at the end of the 3-month treatment was estimated using a transit compartment model based on the simulated fasting glucose values. Two randomized phase 2 studies, one with fixed dosing and the other employing conditional dose titration were conducted. The simulation suggested that (1) Comparable HbA1c lowering with lower hypoglycemia risk occurs with titration compared to fixed-dosing; and (2) A dose range of 50-400 mg BID provides either greater efficacy or lower hypoglycemia incidence or both than glyburide. The predictions were in reasonable agreement with the observed clinical data. The model predicted HbA1c reduction and hypoglycemia risk provided the basis for the decision to focus on the dose-titration trial and for the selection of doses for the demonstration of superiority of LY2599506 to glyburide. The integrated GIG model represented a valuable tool for the evaluation of hypoglycemia incidence.

Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis.

Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 µg (4.86 µmol) or placebo, median 21 months' treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic-pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16-24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 µg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated.

Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials.

BACKGROUND: Duloxetine is indicated for patients with a variety of conditions, and some of these patients may have mild to moderate degrees of renal impairment. Renal impairment may affect the pharmacokinetics of a drug by causing changes in absorption, distribution, protein binding, renal excretion or nonrenal clearance. As duloxetine is highly bound to plasma proteins and its metabolites are renally excreted, it is prudent to evaluate the effect of renal insufficiency on exposure to duloxetine and its metabolites in the systemic circulation. OBJECTIVE: The aim of this study was to evaluate the effects of varying degrees of renal impairment on duloxetine pharmacokinetics in a single-dose phase I study and using pooled steady-state pharmacokinetic data from phase II/III trials. METHODS: In the phase I study, a single oral dose of duloxetine 60 mg was given to 12 subjects with end-stage renal disease (ESRD) and 12 matched healthy control subjects. In the phase II/III trials (n = 463 patients), duloxetine 20-60 mg was given as once- or twice-daily doses. Duloxetine and metabolite concentrations in plasma were determined using liquid chromatography with tandem mass spectrometry. Noncompartmental methods (phase I: duloxetine and its metabolites) and population modelling methods (phase II/III: duloxetine) were used to analyse the pharmacokinetic data. RESULTS: The maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of duloxetine were approximately 2-fold higher in subjects with ESRD than in healthy subjects, which appeared to reflect an increase in oral bioavailability. The C(max) and AUC of two major inactive conjugated metabolites were as much as 2- and 9-fold higher, respectively, reflecting reduced renal clearance of these metabolites. Population pharmacokinetic results indicated that mild or moderate renal impairment, assessed by creatinine clearance (CL(CR)) calculated according to the Cockcroft-Gault formula, did not have a statistically significant effect on pharmacokinetic parameters of duloxetine. Values for the apparent total body clearance of duloxetine from plasma after oral administration (CL/F) in subjects with ESRD were similar to CL/F values in patients with normal renal function or with mild or moderate renal impairment. CONCLUSION: Dose adjustments for duloxetine are not necessary for patients with mild or moderate renal impairment (CL(CR) > or =30 mL/min). For patients with ESRD or severe renal impairment (CL(CR) <30 mL/min), exposures of duloxetine and its metabolites are expected to increase; therefore, duloxetine is not generally recommended for these patients.

Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of approximately 6% from the unity line and described the variability within approximately 4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras-AM concentrations in TRITON-TIMI 38 were comparable with historical data.

Population pharmacokinetics of orally administered duloxetine in patients: implications for dosing recommendation.

OBJECTIVES: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment. METHODS: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131). Patients were given 20-60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups. RESULTS: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (V(d)/F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the V(d)/F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The V(d)/F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups. CONCLUSION: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.

Pharmacokinetics/Pharmacodynamics and the stages of drug development: role of modeling and simulation.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the "learn-and-confirm" paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.

Effect of age on the pharmacokinetics of duloxetine in women.

AIMS: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. METHODS: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day(-1), 30 mg day(-1), or 40 mg day(-1) in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day(-1), 40 mg day(-1), or 80 mg day(-1) in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling program (NONMEM). RESULTS: In Study 1, the elderly (> or = 65 years) exhibited a statistically significant slower elimination rate constant lambdaz compared with younger subjects [elderly-younger difference = -0.022 h(-1)[95% confidence interval (CI) -0.036, -0.008]]. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h(-1) (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies. CONCLUSIONS: Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower lambdaz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.