Population-based Pharmacokinetic Research Articles

Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide.

Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population-based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well-described by a two-compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half-life of tirzepatide was ~5 days and enabled sustained exposure with once-weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.

2551. Assessing Meropenem Concentrations in Children with Septic Shock: Population-Based Pharmacokinetic (PK) Modeling of Meropenem Demonstrates Variability from Acute Kidney (AKI) to Augmented Renal Clearance (ARC)

Abstract Background The primary objective of this study was to characterize meropenem (MERO) pharmacokinetics (PK) in critically ill infants and children with septic shock to develop dosing recommendations to achieve therapeutic drug exposure in this complex population with a spectrum of renal function from augmented renal clearance (ARC) to acute kidney injury (AKI). Methods Children ≥4 weeks old hospitalized with septic shock requiring fluid resuscitation and pressors, receiving MERO 20 mg/kg IV every 8 hr as standard-of-care, were enrolled and studied prospectively from 2019 to 2023. Population PK modeling was used to derive Bayesian post-hoc PK parameters (NONMEM 7.3). Renal biomarkers (serum creatinine [SCr], cystatin C [CYS], serum neutrophil gelatinase-associated lipocalin [NGAL]) were evaluated as covariates. Estimated glomerular filtration rate (e-GFR) was calculated by the modified Schwartz equation. Results A total of 304 MERO serum concentrations were included from 26 participants. Median age was 12.6 yr (range 1.2-19.6); weight 38.4 kg (10-98); SCr 0.36 mg/dL (0.09-2.57); CYS 448.9 mg/d (178.3-1824.1), and NGAL 176.05 ng/mL (29.3-1000). Median MERO serum concentration was 11 mcg/mL (range 0.033-217, interquartile range [IQR] 1.873-37.85). A two-compartment model with allometrically scaled weight on clearance (0.75) best described the data. Significant covariates (final model) were e-GFR, CYS, NGAL, age, diagnosis of appendicitis and albumin. Using the final model, the median CL was 0.15 (range 0.05-0.51, interquartile range [IQR] 0.06-0.25) L/hr/kg and V1 0.20 (0.07-0.57, IQR 0.12-0.31) L/kg, with GFR 139 (23-364, IQR 93-204) mL/min/1.73 m2 (Figure). The distribution of MERO concentrations, CL and GFR across quartiles documents wide variations in renal function observed in septic shock, from AKI to ARC (Figure). Meropenem Serum Concentration, Meropenem Renal Clearance, and Glomerular Filtration Rate, by Quartiles Conclusion Wide variation in MERO plasma exposure was documented in children with septic shock across the spectrum of renal function. GFR-based dosing recommendations may optimize MERO dosing and improve outcomes in this population. This work was supported by NICHD grant 1 R01 HD095547-01 Disclosures Edmund Capparelli, PharmD, Melinta: Advisor/Consultant

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients.

PurposeThe purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose.Patients and MethodsA POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem’s PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval.ResultsThe best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen.ConclusionA population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Implementation of Vancomycin Therapeutic Monitoring Guidelines: Focus on Bayesian Estimation Tools in Neonatal and Pediatric Patients.

The 2020 consensus guidelines for vancomycin therapeutic monitoring recommend using Bayesian estimation targeting the ratio of the area under the curve over 24 hours to minimum inhibitory concentration as an optimal approach to individualize therapy in pediatric patients. To support institutional guideline implementation in children, the objective of this study was to comprehensively assess and compare published population-based pharmacokinetic (PK) vancomycin models and available Bayesian estimation tools, specific to neonatal and pediatric patients. PubMed and Embase databases were searched from January 1994 to December 2020 for studies in which a vancomycin population PK model was developed to determine clearance and volume of distribution in neonatal and pediatric populations. Available Bayesian software programs were identified and assessed from published articles, software program websites, and direct communication with the software company. In the present review, 14 neonatal and 20 pediatric models were included. Six programs (Adult and Pediatric Kinetics, BestDose, DoseMeRx, InsightRx, MwPharm++, and PrecisePK) were evaluated. Among neonatal models, Frymoyer et al and Capparelli et al used the largest PK samples to generate their models, which were externally validated. Among the pediatric models, Le et al used the largest sample size, with multiple external validations. Of the Bayesian programs, DoseMeRx, InsightRx, and PrecisePK used clinically validated neonatal and pediatric models. To optimize vancomycin use in neonatal and pediatric patients, clinicians should focus on selecting a model that best fits their patient population and use Bayesian estimation tools for therapeutic area under the -curve-targeted dosing and monitoring.

Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Early Bayesian Dose Adjustment of Vancomycin Continuous Infusion in Children: a Randomized Controlled Trial.

Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC0-24/MIC≥400 and AUC0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.

Towards Personalized Antithrombotic Treatments: Focus on P2Y12 Inhibitors and Direct Oral Anticoagulants.

Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y12 inhibitors and direct oral anticoagulants. The review will additionally focus on the existing PBPK and POPPK models for these two categories of drugs. Lastly, we address potential scenarios for their implementation in clinics, along with the main limitations and challenges.

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0-∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0-∞ remained using this dosing approach.

The Impact of Capping Creatinine Clearance on Achieving Therapeutic Vancomycin Concentrations in Neurocritically Ill Patients with Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with secondary complications, including infection, and patients with TBI often exhibit augmented renal clearance (ARC). This phenomenon has been associated with subtherapeutic levels of renally cleared drugs such as vancomycin, which is dosed based on body weight and creatinine clearance (CrCl). Many clinicians, however, cap CrCl at 120mL/min/1.73m2 when calculating vancomycin dosing regimens. We hypothesize that capping patient CrCl, as opposed to utilizing the non-capped CrCl, when determining vancomycin dosing schemes results in subtherapeutic serum trough concentrations in patients with TBI. This was a retrospective study of adult patients with TBI admitted between April 2014 and December 2015 who received vancomycin. Population-based pharmacokinetic (PK) parameters using non-capped calculated CrCl and capped CrCl were compared with patient-specific PK parameters based on serum trough concentrations. Thirty-two patients with TBI were included in the study. ARC was suspected in 24 (75%) patients due to a median estimated CrCl at serum trough concentration of 167.3 (127.7-197.7) mL/min. The mean dosing regimen was 17.1 (13.2-19.2) mg/kg every 8 (8-8) h. There was no difference between the median measured trough concentration and predicted value using non-capped CrCl [10.4 (7.1-15.0) vs. 11.5 (7.8-13.7) mcg/mL; p = 0.7986]. The median measured trough concentration was significantly lower than the predicted trough concentration when calculated based on capping the CrCl at 120mL/min/1.73m2 [16.3 (15.3-22.0) vs. 11.5 (7.8-13.7) mcg/mL; p < 0.0001]. Patients with traumatic brain injury appeared to exhibit augmented renal clearance, leading to subtherapeutic vancomycin serum trough concentrations when doses were calculated using the traditional method of capping creatinine clearance at 120mL/min/1.73m2. Instead, utilizing patients' non-capped creatinine clearance when determining a vancomycin dosing regimen is more accurate and provides a better estimation of vancomycin pharmacokinetics and could be applied to other renally excreted medications.

Influence of Bayesian optimization on the performance of propofol target-controlled infusion

BackgroundTarget controlled infusion (TCI) systems use population-based pharmacokinetic (PK) models that do not take into account inter-individual residual variation. This study compares the bias and inaccuracy of a population-based vs a personalized TCI propofol titration using Bayesian adaptation. Haemodynamic and hypnotic stability, and the prediction probability of alternative PK models, was studied. Methods. A double-blinded, prospective randomized controlled trial of 120 subjects undergoing cardiac surgery was conducted. Blood samples were obtained at 10, 35, 50, 65, 75 and 120 min and analysed using a point-of-care propofol blood analyser. Bayesian adaptation of the PK model was applied at 60 min in the intervention group. Median (Absolute) Performance Error (Md(A)PE) was used to evaluate the difference between bias and inaccuracy of the models. Haemodynamic (mean arterial pressure [MAP], heart rate) and hypnotic (bispectral index [BIS]) stability was studied. The predictive performance of four alternative propofol PK models was studied. Results. MdPE and MdAPE did not differ between groups during the pre-adjustment period (control group: 6.3% and 16%; intervention group: 5.4% and 18%). MdPE differed in the post-adjustment period (12% vs. −0.3%), but MdAPE did not (18% vs. 15%). No difference in heart rate, MAP or BIS was found. Compared with the other models, the Eleveld propofol PK model (patients) showed the best prediction performance. Conclusions. When an accurate population-based PK model was used for propofol TCI, Bayesian adaption of the model improved bias but not precision. Clinical trial registrationDutch Trial Registry NTR4518.

Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy.

Application of Reverse Dosimetry to Compare In Vitro and In Vivo Estrogen Receptor Activity

High-throughput screening (HTS) assays may provide an efficient way to identify endocrine-active chemicals. However, nominal in vitro assay concentrations of a chemical may not accurately reflect the blood or tissue levels that cause in vivo effects because in vitro assays do not fully account for chemical pharmacokinetics. In this in vitro-to-in vivo extrapolation (IVIVE) study, we used metabolic clearance and plasma protein binding data with population-based pharmacokinetic (PK) models to quantitatively compare in vitro and in vivo dosimetry for reference chemicals estradiol and bisphenol A, and 230 environmental chemicals that potentially interact with the estrogen receptor (ER) pathway. We first determined the point-of-departure (POD) values from an HTS ER transactivation assay, BG1Luc HTS, and then estimated the daily oral equivalent doses (OEDs) in rats and humans that would result in a steady-state in vivo blood concentration equivalent to the POD values. Where available, we compared the OEDs to the lowest effective doses (LEDs) in rat uterotrophic assays and human exposure values. For all the chemicals with in vivo data, OEDs estimated from POD values were lower than the LEDs in rat uterotrophic assays, suggesting that BG1Luc HTS assay may provide a more conservative hazard estimate for use in risk assessment. Further, human exposure values were generally lower than OEDs estimated from the BG1Luc HTS assay across all environmental chemicals with reported exposure information. In cases where the human OEDs are orders of magnitude lower than the estimated exposures, chemical-induced toxicity appears unlikely. Our modeling approach highlights the importance of PK considerations in ranking endocrine-active chemicals based on in vitro HTS assays.

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors.

To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients. A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK. Unbound MPA concentration-time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min(-1)), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h(-1) (37.4%), 541 l h(-1) (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK. In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.

High Diagnostic Utility of Second-Day Factor VIII Levels to Assess Pediatric Hemophilia A Pharmacokinetics

AbstractAbstract 3368 Background:The role of pharmacokinetic (PK) assessment of factor VIII (fVIII) plasma levels in hemophilia A patients (pts) is evolving. For two decades at our center and many others, full or “modified” PK studies were based on multiple levels drawn before and for several hours following infusion. This required IV access for frequent sampling as well as substantial staff, patient, and parent time. A practical consequence was that PK assessment was reserved for pts with concern for poor factor survival. Recently Björkman, Collins et al reported use of population-based PK sampling to obtain accurate half-life (t1/2) determination by limited blood sampling (2 levels only, 12–36 hours post dose, “Day 2”) in adults with hemophilia A [Haemophilia 16:597, 2010]. The aim of this study was to evaluate the applicability and practical use of these principles in a large pediatric hemophilia clinic, with a long-term goal of individualizing factor VIII dosing. Methods:For this IRB-approved chart review, 27 pts were identified through Hemophilia Center records and a hospital EMR search strategy, who had fVIII PK studies since 2002 at Boston Children’s Hospital. Four of 27 had an inhibitor at the time of assessment and were excluded from analysis. Maximum post-infusion fVIII concentrations (Cmax) were estimated from the TCI Works Program [Björkman, Haemophilia 17:e239, 2011]. Graphical and statistical analyses were conducted in GraphPad Prism 5.01. Graphical models in Prism used non-linear least squares fit to a one phase exponential decay curve with the “terminal plateau” parameter arbitrarily constrained to 0.5% (0.005U/ml fVIII) for severe hemophilia A. Results:Forty sets of PK studies were analyzed from 23 pts, median age 7.9 years, and including 8/23 patients (35%) with former inhibitors. The median z-score for BMI was +0.3; obesity was rare. All FDA approved recombinant fVIII brands were represented. The average t1/2 of fVIII in our pts was 6.8 ± 2.1 hours. 52% (12/23) of patients had PK values only within the first 8 hours after an infusion (plus pre-infusion “trough”). Eight non-inhibitor pts contributed multiple sets of PK to the study, over a maximum time interval of 8 years, with negligible variability over time. Due to the commonly observed rapid early fVIII clearance (“biphasic kinetics”), estimates of t1/2 based on Day 2 time points (after 12–24 h when available) are longer than estimates based on points within the first several hrs post infusion (“Day 1”) for pts in which both “Days” were available. Figure A demonstrates this effect in one pt, and shows t1/2 estimated from early vs. late samples. An example of Day 2 sampling alone is shown in Figure B. Conclusions:Second-day fVIII sampling shows promise in pediatric hemophilia A pts as published for adult pts. Testing our entire prophylaxis population by this method has significant implications for individualized vs. fixed dose prophylactic dosing strategies. In non-inhibitor pts, our center has historically used every-other-day prophylactic fVIII dosing at 25 U/kg usually not modified for individual PK. The recognition that Day 2 sampling is equal or superior to detailed first-day testing could result in manifold improvements in (a) pt satisfaction; (b) ability to test all prophylaxis pts rather than those with perceived bleeding risk; (c) ability to individualize treatment models based on PK assessments; (d) reduced testing cost per pt; and (e) potential large savings on a population basis for factor utilization. Individualized dose tailoring and kinetic analyses offer the potential for better pt health and decreased cost of hemophilia treatment. [Display omitted] Disclosures:Saxena:Bayer: Research Funding; Novo Nordisk: Research Funding. Neufeld:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: DSMB membership, DSMB membership Other; Baxter: Research Funding.

Bottom‐up modeling and simulation of tacrolimus clearance: prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates.

Assessing the efficiency of mixed effects modelling in quantifying metabolism based drug–drug interactions: using in vitro data as an aid to assess study power

The clinical assessment of metabolic drug-drug interactions (mDDI) may involve population-based pharmacokinetic (POPPK) assessment as part of Phase 3 clinical trials. The elements of such POPPK study design have not been linked to prior information from in vitro experiments. Using in vitro-in vivo extrapolation techniques, implemented within Simcyp algorithms, the influence of POPPK study design (sample size, concentration-time data points, proportion of the population receiving a concomitant medication (COMED)) was studied in relation to the inhibitory potency of the each COMED. Steady-state concentrations of a candidate compound (compound X; mainly metabolized by cytochrome P450 enzymes, CYP3A4 and CYP2D6) in the presence and absence of COMEDs (including ketoconazole, fluconazole, quinidine and paroxetine as inhibitors) were analysed using non-linear mixed effect modelling (NONMEM). The NONMEM operator was blind to the nature of the COMEDs and the inhibitory effects on model parameters were classified as either statistically (p>0.01 for a change in objective function) or kinetically (COMED effect>2 fold) significant. Using a population study size of 2000, no false-positive cases were identified and, except in one case, no false-negative interaction was observed when >2.5% of patients had received an interacting COMED. The findings increase the confidence in the ability of the mixed effects modelling approach to identify 'true' interactions. However, they also emphasize the importance of study design and the potential value of using pre-clinical information from in vitro studies. Recent US Food and Drug Administration guidance on mDDI has put more emphasis on the use of in vitro systems for detecting and anticipating such effects. Combining these data with the framework of non-linear mixed effect modelling seems a natural progression in the field of assessing mDDI.

Clinical pharmacology – providing tools and expertise for translational medicine

‘There is an urgent need to develop individuals whohave the ability to combine a firm grounding in theprinciples of basic and clinical pharmacology with themost modern research technologies to addresscomplex (patho)physiological questions’The Wellcome Trust, 2007Those who remember their school Latin will recall theparadigm for regular verbs such as ‘to love’: amo, amare,amavi,amatum–Ilove(present tense), to love (presentinfinitive), I have loved (perfect tense), loved (past parti-ciple). But the paradigm for the verb ‘to carry’ is irregular:ferro,ferre,tuli,latum.It comes,in fact,from three differentroots. And that explains the connection between wordssuch as refer and relate, confer and collate, transfer andtranslate [1].To transfer means to carry over or bring over, and byextension to change over. To translate carries a similarmeaning,to change or adapt to another use.This meaning,which dates from the late 14th century, includes suchimplications as physical or metaphorical transference andthe interchangeability of languages, and it extends themeaning of transfer. ‘Bottom, thou art translated,’ saysSnug in

Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model

Limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to use in methadone dosing recommendations in pediatric patients for either opioid abstinence or analgesia. Considering the extreme inter-individual variability of absorption and metabolism of methadone, population-based PK would be useful to provide insight into the relationship between dose, blood concentrations, and clinical effects of methadone. To address this need, an age-dependent physiologically based pharmacokinetic (PBPK) model has been constructed to systematically study methadone metabolism and PK. The model will facilitate the design of cost-effective studies that will evaluate methadone PK and PD relationships, and may be useful to guide methadone dosing in children. The PBPK model, which includes whole-body multi-organ distribution, plasma protein binding, metabolism, and clearance, is parameterized based on a database of pediatric PK parameters and data collected from clinical experiments. The model is further tailored and verified based on PK data from individual adults, then scaled appropriately to apply to children aged 0-24 months. Based on measured variability in CYP3A enzyme expression levels and plasma orosomucoid (ORM2) concentrations, a Monte-Carlo-based simulation of methadone kinetics in a pediatric population was performed. The simulation predicts extreme variability in plasma concentrations and clearance kinetics for methadone in the pediatric population, based on standard dosing protocols. In addition, it is shown that when doses are designed for individuals based on prior protein expression information, inter-individual variability in methadone kinetics may be greatly reduced.