Population Pharmacodynamic Model Research Articles

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

BackgroundChronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.Methods619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.ResultsThe effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min−1 in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.ConclusionsSimulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.

Population pharmacometrics in support of analgesics studies

Population pharmacometric modeling is used to explain both population trends as well as the sources and magnitude of variability in pharmacokinetic and pharmacodynamics data; the later, in part, by taking into account patient characteristics such as weight, age, renal function and genetics. The approach is best known for its ability to analyze sparse data, i.e. when only a few measurements have been collected from each subject, but other benefits include its flexibility and the potential to construct more detailed models than those used in the traditional individual curve fitting approach. This review presents the basic concepts of population pharmacokinetic and pharmacodynamic modeling and includes several analgesic drug examples. In addition, the use of these models to design and optimize future studies is discussed. In this context, finding the best design factors, such as the sampling times or the dose, for future studies within pre-defined criteria using a previously constructed population pharmacokinetic model can help researchers acquire clinically meaningful data without wasting resources and unnecessarily exposing vulnerable patient groups to study drugs and additional blood sampling.

Basic Concepts in Population Modeling, Simulation, and Model‐Based Drug Development: Part 3—Introduction to Pharmacodynamic Modeling Methods

Population pharmacodynamic (PD) models describe the time course of drug effects, relating exposure to response, and providing a more robust understanding of drug action than single assessments. PD models can test alternative dose regimens through simulation, allowing for informed assessment of potential dose regimens and study designs. This is the third paper in a three-part series, providing an introduction into methods for developing and evaluating population PD models. Example files are available in the Supplementary Data.

The Use of Population Pharmacokinetic and Pharmacodynamic Modeling and Simulation in Anti-Osteoporotic Drug Development: A Perspective

The Use of Population Pharmacokinetic and Pharmacodynamic Modeling and Simulation in Anti-Osteoporotic Drug Development: A Perspective

Differential analysis of transient increases of serum cTnI in response to handling in rats.

Serum cardiac troponins are the key biomarkers of myocardial necrosis in humans and in preclinical species. The use of ultrasensitive assays for serum cardiac troponin I (cTnI) as a biomarker in safety studies is hampered by interindividual differences. In this study, we investigated the effect of handling procedures on serum cTnI and explored modeling and simulation approaches to mitigate the impact of these interindividual differences. Femoral-catheterized male Crl:WI(Han) rats (n = 16/group) were left undisturbed in their cages with no handling; subjected to 5 min of isoflurane/O2 anesthesia (A); or placed into a rodent restrainer followed by simulated tail vein injection (RR). Serum cTnI concentrations were assessed over a 24-h period using an ultrasensitive assay, and the study was repeated for confirmation. The mean serum cTnI concentration pre-procedure was 4.2 pg/mL, and remained stable throughout the duration of the study in the rats submitted to the A procedure. Serum cTnI concentrations increased transiently after the RR procedure with a median time to maximum concentration (Tmax), of 1 and 2 h and a mean maximum value concentration (Cmax), of 53.0 and 7.2 pg/mL in the initial and repeat studies, respectively. A population pharmacodynamic model identified interindividual, procedure- and study-specific effects on serum cTnI concentrations in rats. It is concluded that a modeling and simulation approach more appropriately describes and statistically analyzes the data obtained with this ultrasensitive assays.

Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO‐5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

The evolving role of the Journal of Clinical Pharmacology and its contributions to the discipline

This issue of the Journal of Clinical Pharmacology, the official publication of the American College of Clinical Pharmacology, represents my final effort as its Editor-in-Chief for the past 5 years. Reflecting on the discipline, Clinical Pharmacology continues to evolve at an accelerating pace. Papers published in the Journal have in the past and continue to reflect advances in the discipline. Concepts published only 5 years ago not unexpectedly are incorporated into today's clinical trial protocols and are often no longer perceived as innovative contributions to the discipline. I am confident that this evolution will continue into the future under the leadership of the incoming Editor-in-Chief, Dr. Joseph Bertino. The Journal has changed considerably over the past 5 years. Review articles are appearing more often, while maintaining the majority of its content as original studies on human pharmacological advances, both pharmacokinetic and pharmacodynamic. We have had the opportunity to publish important supplements related to the growth of pharmacometrics,1 and to revisit the confounding impact of renal impairment on optimization of drug therapy.2 There is an increasing presence of drug studies from the pediatric cohort and of results from patient investigations, for whom new and improved drug treatment strategies continue to be developed. Ultimately, these kinds of papers should impact dramatically on optimization of therapeutics. It is reassuring to see the increasing inclusion of genetic and other biomarker data as parameters that may further address the ultimate goal of individualized drug therapy. Evolution of population pharmacokinetic and pharmacodynamic modeling strategies should allow for improved paradigms for drug treatment of high risk populations, especially where sample access is considerably limited. The increasing success of biological therapies will pose unique challenges to clinical pharmacologists, and provide substantial opportunities for innovation in clinical pharmacokinetic and pharmacodynamic clinical trials. Submissions of manuscripts to the Journal for consideration continue to increase and now exceed 500 yearly, making it much more difficult to select among the many excellent papers for the published content of monthly issues, while reflecting the diversity of the discipline. At this point it is essential to thank my Associate Editors, Drs. Hartmut Derendorf and Michael Reed for their wise counsel, my Editorial Board for its thorough and insightful peer review of the many manuscripts assigned to them, and many guest reviewers for manuscripts where content is reflecting areas of growth and change in the discipline. Of course, all of these efforts were orchestrated via the outstanding efforts of our Managing Editor, Ms. Marjory Spraycar, and Assistant Managing Editor, Ms. Elizabeth Marshall. Our Journal remains a widely read and cited source of knowledge directed at the improvement of patient quality of life when drug therapies are chosen as interventions to minimize consequences of pathological processes. I am grateful to all for having been offered the opportunity to contribute to such a laudable goal.

Population Pharmacodynamic Modeling of Exenatide After 2-Week Treatment in STZ/NA Diabetic Rats

The purpose of this study is to investigate the effect of exenatide on glycemic control following two administration routes in a streptozotocin/nicotinamide (STZ/NA)-induced diabetic rat model, and to develop a pharmacodynamic model to better understand the disease progression and the action of exenatide in this experimental system. Two groups of STZ/NA-induced diabetic rats were treated for 2 weeks with 20 (μg/kg/day) of exenatide, either by continuous subcutaneous (SC) infusion or two SC injections daily. Disease progression was associated with slower glucose utilization. Fasting blood glucose was significantly reduced by 30 mg/dL in both treatment groups at the end of 2 weeks. A subsequent intravenous glucose tolerance test (IVGTT) confirmed an improved glucose tolerance in both treatment groups; however, overall glycemic control was similar between groups, likely due to the relatively low and short-term drug exposure. A population indirect response model was successfully developed to simultaneously describe the STZ/NA-induced disease progression, responses to an IVGTT, and exenatide effects on these systemic challenges. The unified model includes a single set of parameters, and the cumulative area under the drug-receptor concentration curve was used as a unique driving force to account for systemic effects long after drug elimination.

Population Pharmacodynamic Modeling of Hyperglycemic Clamp and Meal Tolerance Tests in Patients with Type 2 Diabetes Mellitus

In this study, glucose and insulin concentration-time profiles in subjects with type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic clamp (HGC) conditions were co-modeled simultaneously. Blood glucose and insulin concentrations were obtained from 20 subjects enrolled in a double-blind, placebo-controlled, randomized, two-way crossover study. Patients were treated with palosuran or placebo twice daily for 4 weeks and then switched to the alternative treatment after a 4-week washout period. The MTT and HGC tests were performed 1 h after drug administration on days 28 and 29 of each treatment period. Population data analysis was performed using NONMEM. The HGC model incorporates insulin-dependent glucose clearance and glucose-induced insulin secretion. This model was extended for the MTT, in which glucose absorption was described using a transit compartment with a mean transit time of 62.5 min. The incretin effect (insulin secretion triggered by oral glucose intake) was also included, but palosuran did not influence insulin secretion or sensitivity. Glucose clearance was 0.164 L/min with intersubject and interoccasion variability of 9.57% and 31.8%. Insulin-dependent glucose clearance for the HGC was about 3-fold greater than for the MTT (0.0111 vs. 0.00425 L/min/[mU/L]). The maximal incretin effect was estimated to enhance insulin secretion 2-fold. The lack of palosuran effect coupled with a population-based analysis provided quantitative insights into the variability of glucose and insulin regulation in patients with T2DM following multiple glucose tolerance tests. Application of these models may also prove useful in antihyperglycemic drug development and assessing glucose-insulin homeostasis.

A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis

Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.

Pharmacokinetic/pharmacodynamic evaluation of the efficacy and safety of daptomycin against Staphylococcus aureus

Daptomycin is a novel lipopeptide exhibiting concentration-dependent bactericidal activity against multidrug-resistant Gram-positive pathogens, including MRSA. Approval of daptomycin is granted at 4–6mg/kg once daily, however off-label use of doses up to 12mg/kg daily has been utilised without evidence of significant toxicity. Our aim was to optimise daptomycin regimens by assessing the probability of bacteriological efficacy (pTA) and toxicity (pTOX) at various MICs using Monte Carlo simulation (MCS) techniques. Population pharmacokinetic, pharmacodynamic and toxicodynamic models were developed based on current literature. MCS was performed for 10000 patients, who were assigned true weight and creatinine clearances, and were infected with four Staphylococcus aureus strains at each MIC. Bacteriostatic and bactericidal %pTA was calculated following administration of 6, 8, 10 and 12mg/kg daptomycin; activity was deemed adequate at %pTA≥90%. Considerable pharmacodynamic variability was observed in derived AUC/MIC targets between strains. Bacteriostatic targets were adequately attained against all strains at MIC≤1mg/L with daptomycin >6mg/kg. However, bactericidal target attainment was only achieved against all strains at the lowest MIC of 0.5mg/L with daptomycin >8mg/kg. At MIC=2mg/kg, bactericidal target attainment was extremely poor even at the highest dose of 12mg/kg. pTOX increased from 3.31% to 17.7% following exposure to 6mg/kg to 12mg/kg daily, respectively. Formal benefit:risk analyses favoured doses of 10mg/kg against infections with MIC<2mg/L, whilst modest improvements in activity at 12mg/kg could not justify the marked increase in pTOX.

Population Pharmacokinetic and Pharmacodynamic Modeling of Acetazolamide in Peritoneal Dialysis Patients and Healthy Volunteers

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. Both PK and PD are significantly altered in dialysis patients.

Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression

Presynaptic and post-synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post-synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression. In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week⁻¹ to 20 mg) in a randomized, double-blind, parallel group, 8 week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups. A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (γ, 95% confidence interval [CI]) best described the data (γ(memantine) = 1.8, 95% CI 0.9, 3.6), γ(placebo) = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5). This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.

Model-based Dose Selection for Phase III Rivaroxaban Study in Japanese Patients with Non-valvular Atrial Fibrillation

The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.

Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw

We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ. Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects. Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P < 0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P < 0.001), older age (76 vs 70 years, P < 0.001), and Asian race (49% vs 14%, P < 0.001). Our model accurately discriminated BRONJ cases from controls among patients on BP therapy.

Population Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody, Siltuximab (CNTO 328), in Patients with B-Cell Non-Hodgkin’s Lymphoma, Multiple Myeloma, or Castleman’s Disease

AbstractAbstract 1365 IntroductionSiltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. MethodsPK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. ResultsThe mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. ConclusionThe population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures:Xie:Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.

Population PK/PD analysis of metformin using the signal transduction model

Metformin, a biguanide glucose lowering agent, is commonly used to manage type 2 diabetes. The molecular mechanisms of metformin have not been fully identified, but turnover of biomarkers such as glucose and signalling pathways or translocation of glucose transporters are closely related to the glucose-lowering effects of metformin. The PK/PD of metformin have been investigated in healthy humans and patients with type 2 diabetes mellitus and modelling has been performed using an indirect response model. The purpose of this investigation was to develop a population PK/PD model for metformin using a signal transduction model in healthy humans and predict the PK/PD profile in patients with type 2 diabetes. The aim was to compare a previous model (a biophase model) with the signal transduction model, and use a more appropriate model to follow the actions of metformin. Additionally, our developed model was appropriate to predict the time course of plasma metformin and fasting plasma glucose (FPG) concentrations in patients with type 2 diabetes. To our knowledge, this is the first published population PK/PD analysis using the signal transduction model for metformin. AIMS To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500 mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes. Following the oral administration of 500 mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes. Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6 l h(-1) (4.18%), 113 l (56.6%) and 0.41 h(-1) , respectively. Covariate analyses revealed that creatinine clearance (CL(CR) ) significantly influenced metformin: CL/F= 52.6 × (CL(cr) /106.5)(0.782) . The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68 µg ml(-1) (3.89%), 0.5 h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values. The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision.

Modeling of the LDL cholesterol-lowering effect of atorvastatin in Korean dyslipidemic patients and non-patient volunteers

The aim of this study was to develop a longitudinal pharmacodynamic model describing the time-courses of low-density lipoprotein cholesterol (LDL) profiles during and after atorvastatin treatment in Korean dyslipidemic patients and non-patient volunteers. 15 dyslipidemic patients and 11 non-patient volunteers with no prior therapy participated in a parallel, 2-step dose escalation study. Subjects received atorvastatin doses ranging from 10 to 80 mg for 42 days (dyslipidemic patients) or 10 mg for 21 days (non-patient volunteers). Plasma samples were collected before and during the treatment period and up to 2 weeks after the last administration. A population pharmacodynamic model was built using the NONMEM software package. An indirect response model consisting of production in hepatocyte and elimination from plasma stimulated by atorvastatin described the LDL time-course. The typical population value of the estimated dose producing 50% of maximal stimulation on LDL elimination (SD50) for dyslipidemic patients was 11.9 mg, which was about 6 times higher than that of non-patient volunteers (2.0 mg). A longitudinal population pharmacodynamic model for the LDL-lowering effect of atorvastatin in both dyslipidemic patients and non-patient volunteers was developed. This could help guide optimal therapies according to the target population.

Evaluation of a Pharmacology-Driven Dosing Algorithm of 3-Weekly Paclitaxel Using Therapeutic Drug Monitoring

Severe neutropenia is the most frequent and important toxicity of 3-weekly paclitaxel and puts patients at substantial risk of infectious complications. It is well known that the time during which paclitaxel plasma concentrations exceed 0.05 μmol/L (T(C>0.05)) correlates with the extent of neutropenia. This study was initiated to develop a dosing algorithm that would be able to reduce severe neutropenia by targeting an individual paclitaxel T(C>0.05) between 26 and 31 hours, and could be validated in a prospective randomized trial by comparing it to conventional dosing of paclitaxel. Paclitaxel plasma concentration-time (n = 273) and absolute neutrophil count (ANC) data (152 of the 273 patients) were pooled from two previous studies and submitted to population pharmacokinetic and pharmacodynamic modelling using nonlinear mixed-effects modelling software NONMEM® version VII. To fit the data, we used a previously described 3-compartment model with saturable elimination and distribution, coupled to a semiphysiological model with a linear function to describe the myelotoxic effect of paclitaxel (E(paclitaxel)) on circulating neutrophils (neutropenia). Patient age, sex, body surface area (BSA), bilirubin and renal function were tested as potential covariates on the maximum elimination capacity of paclitaxel (VM(EL)). Limited sampling strategies were tested on the pharmacokinetic model for their accuracy to predict paclitaxel T(C>0.05). Subsequently, we proposed a first-cycle dosing algorithm that accounted for BSA, patient age and sex, while later cycles accounted for the previous-cycle paclitaxel T(C>0.05) (target: 26 to 31 hours) and ANC nadir to adapt the paclitaxel dose for the next treatment cycle. To test the adequacy of the proposed dosing algorithm, we used extensive data simulations on the final pharmacokinetic/pharmacodynamic model, generating datasets of 1000 patients for six subsequent treatment cycles. Grade 4 neutropenia was tested as a potential endpoint for a prospective clinical trial and simulated for two scenarios, i.e. conventional dosing of paclitaxel 200 mg/m(2) every 3 weeks, and personalized, pharmacology-driven dosing as outlined above. Concentration-time data for paclitaxel were adequately described by the 3-compartment model. Also, individual ANC counts were adequately described by the semiphysiological model using a linear function to describe E(paclitaxel) on neutropenia. Patient age, sex, bilirubin and BSA were significant and independent covariates on the elimination of paclitaxel. Paclitaxel VM(EL) was 16% higher in males than in female patients, and a 10-year increase in age led to a 13% decrease in VM(EL). A single paclitaxel plasma concentration 24 hours after the start of infusion was adequate to predict paclitaxel T(C>0.05) (root squared mean error [RSME] = +0.5%), and the addition of an end-of-infusion sample did not further improve precision (RSME = -0.6%). Data simulations on the final pharmacokinetic/pharmacodynamic model and using the proposed dosing algorithm resulted in a first-cycle paclitaxel dose ranging from 150 to 185 mg/m(2) for women and from 165 to 200 mg/m(2) for men. Dose adaptations for cycles two to six ranged from -40% to +30%, with a final median paclitaxel dose of 167 mg/m(2) (range 76 to 311 mg/m(2)). When compared with conventional dosing (paclitaxel 200 mg/m(2) every 3 weeks), personalized dosing reduced grade 4 neutropenia in cycle one from 15% to 7%, and further to 4% in cycle 2. This study proposes a pharmacology-driven dosing algorithm of 3-weekly paclitaxel to reduce the incidence of grade 4 neutropenia. A randomized clinical trial comparing this dosing algorithm with conventional BSA-based dosing of paclitaxel in patients with advanced non-small cell lung cancer is currently ongoing.

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.