Population Pharmacodynamic Model Research Articles

Pharmacokinetic-pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients.

AimsTo characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation.MethodsPlatelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily.ResultsPlatelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l–1. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations.ConclusionsIn patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak‐to‐trough variability.

A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients

Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules.

A pharmacodynamic model of respiratory rate and end-tidal carbon dioxide values during anesthesia in children.

It is essential to monitor the end-tidal carbon dioxide (ETCO2) during general anesthesia and adjust the tidal volume and respiratory rate (RR). For the purpose of this study, we used a population pharmacodynamic modeling approach to establish the relationship between RR versus ETCO2 data during general anesthesia in children, and to identify the clinical variables affecting this relationship. A prospective observational study was designed to include 51 patients (aged ≤ 12 years), including users of antiepilepticdrugs (levetiracetam, valproic, or phenobarbital(n = 21)) and non-users (n = 30), scheduled to receive general anesthesia during elective surgery. When the ETCO2 was at 40 mmHg, the RR was adjusted 1 breath per every 2 min until the ETCO2 was 30 mmHg and recovered to 40 mmHg. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the RR-ETCO2 relationship. As RR varied from 3 to 37 breaths per minute, the ETCO2 changed from 40 to 30 mmHg. Hysteresis between the RR and ETCO2 was observed and accounted for when the model was developed. The Ce50 (RR to achieve 50% of maximum decrease in ETCO2; i.e. 35 mmHg) was 20.5 in non-users of antiepileptic drugs and 14.9 in those on antiepileptic drug medication. The values of γ (the steepness of the concentration-response relation curve) and keo (the first-order rate constant determining the equilibration between the RR and ETCO2) were 7.53 and 0.467 min-1, respectively. The Ce50 and ETCO2 data fit to a sigmoid Emax model. In conclusion, the RR required to get the target ETCO2 was much lower in children patients taking antiepileptic drugs than that of non-user children patients during the general anesthesia.

Characterization of changes in HbA1c in patients with and without secondary failure after metformin treatments by a population pharmacodynamic analysis using mixture models

The objective of the present study was to develop a population pharmacodynamic (PPD) model to describe the glycated hemoglobin (HbA1c)-lowering effects of metformin in type 2 diabetes mellitus patients with and without secondary failure and to characterize changes in HbA1c levels in the two subpopulations using a mixture model. Information on patients was collected retrospectively from electronic medical records. In this study, the mixture model was used to characterize the bimodal effects of metformin. A PPD analysis was performed using NONMEM 7.3.0. A physiological indirect response model, based on 829 HbA1c levels of 69 patients, described the time course for the HbA1c-lowering effects of metformin. Evidence for the different effectiveness of metformin subpopulations was provided using the mixture model. In the final PPD model, the inhibition effect was constant over a study duration in a patient subpopulation without secondary failure. In contrast, the inhibition effect decreased as a function of time after start of metformin treatment in a subpopulation with secondary failure. These results indicated that HbA1c improvements appeared to deteriorate over time in patients with secondary failure. In a PPD analysis of metformin, it was possible to assign patients with secondary failure using the mixture model.

Abstract P-483: DOSING RECOMMENDATION OF TRICHLOFOS AND CHLORAL HYDRATE BASED ON POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS IN PEDIATRIC INTENSIVE CARE PATIENTS

Aims & Objectives: The objective of this study is to develop an age-specific dosing recommendation for triclofos and chloral hydrate based on population pharmacokinetic and pharmacodynamic modeling and simulation of the active metabolite of these drugs, trichloroethanol(TCOH), in pediatric intensive care patients. Methods The pharmacokinetic and pharmacodynamic analysis was conducted on 171 serum concentrations of TCOH and 242 COMFORT behavior score from 55 children aged four months to four years. An optimal schedule for pharmacokinetic sampling was determined using Simcyp® Simulator. Plasma TCOH concentrations were measured by the GC-MS method. Population pharmacokinetic parameters were estimated by NONMEM®. The cutoff concentration of TCOH to achieve COMFORT behavior score =<16 was determined by receiver operating characteristic curve analysis. The optimal doses of triclofos and the chloral hydrate for children in each age group were determined based on dosing simulation. Results Inter-individual differences in clearance of TCOH was largely attributed to body weight and total bilirubin concentration. All patients with high total bilirubin concentrations were less than one month of age. TCOH concentration and age were associated with sedation in the logistic regression model. Doses of triclofos and chloral hydrate need to be decreased in children less than one month of age and those with high total bilirubin concentrations. The results of this study suggest that total bilirubin concentrations may able to serve as an indicator of the maturation of TCOH clearance. Conclusions The doses of triclofos and chloral hydrate in pediatric intensive care patients should be titrated according to age and total bilirubin concentration.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

AbstractThe noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia.

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test.

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0–128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid Imax model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

Population pharmacodynamics of cilostazol in healthy Korean subjects.

Cilostazol is used for the treatment of intermittent claudication, ulceration and pain. This study was conducted to develop a population pharmacodynamic (PD) model for cilostazol's closure time (CT) prolongation effect in healthy Korean subjects based on a pharmacokinetic (PK) model previously developed. PD data were obtained from 29 healthy subjects who participated in a study conducted in 2009 at Severance Hospital. The PK model used was a two-compartment model with first order absorption. CT data were best described by a turnover model with a fractional turnover rate constant (Kout) inhibited by drug effects (Eff), which were represented by a sigmoid Emax model [Eff = Emax · Cγ / (EC50γ+Cγ)] with Emax being maximum drug effect, EC50 drug plasma concentration at 50% of Emax, C drug plasma concentrations, and γ the Hill coefficient. For the selected PD model, parameter estimates were 0.613 hr−1 for Kout, 0.192 for Emax, 730 ng/ml for EC50 and 5.137 for γ. Sex and caffeine drinking status significantly influenced the baseline CT, which was 85.36 seconds in male non-caffeine drinkers and increased by 15.5% and 16.4% in females and caffeine drinkers, respectively. The model adequately described the time course of CT. This was the first population PD study for cilostazol's CT prolongation effect in a Korean population.

Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients.

AimsMidazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response.MethodA population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check.ResultsThe effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability.ConclusionWe were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure.

Population Pharmacodynamic Analysis of Uric Acid-Lowering Effects of Febuxostat Based on Electronic Medical Records in Two Hospitals.

The aim of this study was to develop a population pharmacodynamic (PPD) model to describe uric acid (UA)-lowering effects in patients treated with febuxostat based on electronic medical records in 2 independent hospitals (university and city hospitals). Interhospital differences in the PPD model were also evaluated. We conducted the following 2 approaches to build the PPD models. A PPD model was developed separately using individual hospital data, and structural models and covariates between the two hospitals were compared (approach A). Another PPD model was developed using all available data from both hospitals, and differences between the 2 hospitals were evaluated by performing a covariate analysis on all PPD parameters (approach B). PPD analyses were performed by NONMEM using data from 358 patients. In both approaches, one indirect response model was established. In approach A, 2 diuretics (loops and thiazides) and renal function tests (Scr or BUN) were selected as covariates for the UA baseline level (serum UA levels just before the febuxostat treatment), whereas 2 diuretics and BUN were selected in approach B. A covariate analysis indicated that loops and thiazides increased UA baseline levels by 7%-14% and 6%-11%, respectively. In approach B, "hospital" was identified as a significant covariate for the UA baseline level; the baseline level was 7% higher in the city hospital. A PPD analysis may provide a precise description of the time course of the UA-lowering effects of febuxostat and quantitatively detect an interhospital difference in the UA baseline level.

Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5'-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC50) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration; therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

Levodopa in Parkinson's Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis.

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population. This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease. A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated. A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale. This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A human challenge model for respiratory syncytial virus kinetics, the pharmacological effect of a novel fusion inhibitor, and the modelling of symptoms scores

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, and is a major cause of hospital admissions and death in young children. Limited treatments currently exist that can prevent or minimise exacerbation of the disease. The aims of this work were: 1) to develop a population pharmacodynamic model to describe RSV kinetics (RSVK) in nasal lavage, 2) evaluate the impact of an investigational fusion inhibitor, JNJ-53718678, on RSVK, and 3) determine the relationship between RSVK and symptoms scores. The best model to fit the RSVK data was a target-cell limited viral kinetics model previously developed for influenza A infections (Baccam et al., 2006), which included a series of compartments for infected, non-producing and infected, and producing cell populations. The model was adapted to account for longer incubation times seen in RSV, by including 4 additional transit compartments, with the virus elimination rate constant and initial number of target cells fixed to literature values to ensure model parameter identifiability. Between-subject variability was included on the infection rate constant and virus production rate constant. The effect of JNJ-53718678 on RSVK was best described by a non-dose dependent transformation of the infectious virions into a non-infectious state, with a proportional odds model successfully describing symptoms scores, using individual model predicted viral loads as predictor.

Population Pharmacokinetic and Pharmacodynamic Modeling of Etelcalcetide in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.

Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2.5 to 60mg. A semi-mechanistic model was used to describe the relationship between etelcalcetide, PTH, and Ca. This model included the role of PTH in Ca regulation, the feedback of Ca onto PTH production via the CaSR, and the activity of etelcalcetide plasma levels in increasing the sensitivity of the CaSR to Ca via the cooperative binding model. The impact of relevant covariates was evaluated by stepwise forward/backward selection. Model evaluation was based on standard goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Simulation was conducted to evaluate titrated dosing regimens. The time courses of etelcalcetide, PTH, and Ca were well-described by the model. The clearance and central volume of distribution (Vc) of etelcalcetide were 0.472L/h and 49.9L, respectively, while estimates of the turnover half-lives of PTH and Ca were 0.36 and 23h, respectively. The extent of interindividual variability in model parameters was low to moderate (6-67%), and no covariates were identified as significant predictors of PK and PD variability. pcVPCs confirmed the predictive ability of the model. The current analysis confirms the putative mechanism of action of etelcalcetide as an allosteric activator of CaSR. Simulations showed that dose titration of etelcalcetide, rather than fixed dose, is needed to effectively decrease the PTH level in patient populations.

A two-step deconvolution-analysis-informed population pharmacodynamic modeling approach for drugs targeting pulsatile endogenous compounds

Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, Cmax). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach. Pulse frequency and pulse times were obtained by deconvolution analysis of 24 h GH profiles. The estimated pulse times then informed a non-linear mixed effects population pharmacodynamic model in NONMEM V7.3. The population parameter estimates were used to perform simulations that show agonistic and antagonistic drug effects on the secretion of GH. Additionally, a clinical trial simulation shows the application of this method in the quantification of a hypothetical drug effect that inhibits GH secretion. The GH profiles were modeled using a turnover compartment in which the baseline secretion, kout, pulse secretion width, amount at time point 0 and pulse amplitude were estimated as population parameters. Population parameters were estimated with low relative standard errors (ranging from 2 to 5%). Total body water (%) was identified as a covariate for pulse amplitude, baseline secretion and the pulse secretion width following a power relationship. Simulations visualized multiple gradients of a hypothetical drug that influenced the endogenous secretion of GH. The established model was able to fit and quantify the highly variable individual 24 h GH profiles over time. This pharmacodynamic model can be used to quantify drug effects that target other endogenous pulsatile compounds.

A pharmacodynamic modelling and simulation study identifying gender differences of daily olanzapine dose and dopamine D2-receptor occupancy

Background: Gender differences in treatment response rates for patients treated with antipsychotics are known. However, the literature lacks a pharmacodynamic model to allow for gender-based clinical trial simulations from modelling parameters for Olanzapine and dopamine D2 receptor occupancy. Thus, the primary aim of this analysis is to test and quantify the effect of gender on the pharmacodynamics of Olanzapine.Methods: Population pharmacodynamic modelling was performed using non-linear mixed effects modelling in MONOLIX, while the Clinical Trial Simulations were performed using R for statistical programming. The pharmacometric analysis is based on a pooled data approach from three clinical studies where patients were diagnosed with schizophrenia and one clinical study where the patients were diagnosed with bipolar disorder.Results: Olanzapine D2RO was modelled using an Emax model in a study population of 70 patients. Population pharmacodynamic parameters were estimated to be: Emax = 85.6% (RSE = 3%), ED50-Men = 5.15 mg/day (RSE = 14) and ED50-Women = 2.38 mg/day (RSE = 34%), with the p-value = 0.037 for the gender-stratified ED50 results.Conclusion: The pharmacometrics analysis and model-based dosing simulations suggest that, in order to achieve 70% D2RO, women require a 10 mg/day dose and men require approximately a 20 mg/day dose of Olanzapine. Further, clinical implications exist suggesting that clinicians should factor patient gender when considering both a starting dose, as well a, a maintenance dose for patients prescribed Olanzapine due to quantifiable gender-differences of striatal dopamine D2 receptor occupancy.

Quantitative model for the blood pressure-lowering interaction of valsartan and amlodipine.

The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10mg amlodipine and 160mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3. A two-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an Imax model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1 +D2 ) +ALPHA×(D1 × D2 ). D1 and D2 are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were -0.171 (95% CI: -0.218, -0.143) for SBP and -0.0312 (95% CI: -0.07739, -0.00283) for DBP. These infra-additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes. PKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra-additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified.

Population Pharmacodynamic Model for Bayesian Prediction of Myelosuppression Profiles Based on Routine Clinical Data after Gemcitabine and Carboplatin Treatment

Background: Hematological toxicity is a serious adverse event and is often a dose-limiting factor in anticancer drugs. The objective of the present study was to develop a modeling and simulation (M&S) procedure for predictions of time course profiles of blood cell counts that reflect myelosuppression profiles. Methods: A method for Bayesian prediction of myelosuppression profiles during chemotherapy using a population pharmacodynamic model is proposed, and predictabilities of nadir values and times to nadir (T_nadir) after gemcitabine and carboplatin treatment were evaluated. The model is based on an equation for Erlang distribution, which we previously proposed, and it explains time course profiles of platelet (PLT), red blood cell (RBC) and white blood cell (WBC). Results and Conclusion: PLT, RBC and WBC counts were retrospectively collected from 61 time courses (a total of 472 points) of 27 cancer patients. Predictive performance by a one-point Bayesian prediction was evaluated using data from day 8 in consideration of applicability to outpatients. Some good predictability was obtained for nadir values with some exceptions for PLT and RBC, whereas the predictability of T_nadir was insufficient. Although the predictability was not acceptable enough, this M&S approach could be used for supportive care during cancer chemotherapy.