Final Population Pharmacokinetic Model Research Articles

Population pharmacokinetics of ruxolitinib in children with hemophagocytic lymphohistiocytosis: focus on the drug-drug interactions.

The optimal dose regimen of ruxolitinib (RUX) in children with hemophagocytic lymphohistiocytosis (HLH) remains to be determined. The aim was to develop and verify a population pharmacokinetic (PPK) model, and then provide references for the optimization of dose regimen of RUX in children with HLH. A total of 189 RUX concentrations from 32 children were included. The PPK model was established using the nonlinear mixed-effects model approach. Predictive performance and stability of the final PPK model were evaluated. The exposure of RUX in different clinical scenarios was simulated through Monte Carlo simulations. A one-compartment model with first-order absorption and linear elimination was identified to describe the disposition of RUX. The absorption rate constant (Ka) in the final PPK model was 1.05h-1, and the apparent clearance (CL/F) and volume of distribution (V/F) were 9.80 L/h and 30.6 L, respectively. Coadministration with triazoles (TZS) and azithromycin (AZM) resulted in approximately 31.0% and 32.4% reductions in the CL/F of RUX, respectively. Multiple evaluation procedures showed satisfactory predictive performance and stability of the final model. Monte Carlo simulations showed that the exposure of RUX was significantly affected by the coadministration with TZS and/or AZM under different clinical scenarios. For the first time, a PPK model of RUX in children with HLH was developed and evaluated. The coadministration with TZS and/or AZM were found to reduce the clearance of RUX in children. These findings could provide new insights for the precise treatment of RUX in children with HLH.

Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism.

Objective: The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy. Methods: A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients. Results: A significant effect of the patient age and ABCB1 genotypes was observed on the VPA oral clearance (CL/F) in the final PPK model. Compared with patients with the ABCB1 rs3789243 AA genotype, CL/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and ABCB1 genotype was constructed based on the final PPK model. Conclusion: This study quantitatively investigated the effects of patient age and ABCB1 rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.

A Population Pharmacokinetic (PopPK) Model to Characterize Efanesoctocog Alfa (BIVV001) Factor VIII (FVIII) Activity Levels in Patients with Severe Hemophilia A

Introduction Efanesoctocog alfa (formerly BIVV001) is a new class of FVIII replacement therapy uniquely engineered to decouple recombinant FVIII from endogenous von Willebrand factor (VWF) and overcome the VWF-imposed half-life ceiling. Once-weekly efanesoctocog alfa provides high sustained FVIII activity in the normal to near-normal range for most of the week and demonstrated superior bleed protection compared with prior FVIII prophylaxis. FVIII activity data have been collected from 5 clinical studies (Phase 1/2a single- and repeat-dose studies [NCT03205163 and EudraCT 2018-001535-51, respectively] in adults, and Phase 3 studies in adults and adolescents ≥12 years of age [XTEND-1, NCT04161495] and children ≥1 year to <12 years [XTEND-Kids, NCT04759131] and Phase 3 long-term extension study [XTEND-ed, NCT04644575]). We aimed to develop a popPK model to characterize FVIII activity after efanesoctocog alfa dosing, identify intrinsic and extrinsic factors affecting pharmacokinetics (PK), and assess PK variability. Methods FVIII activity levels used to develop the popPK model were measured by the one-stage clotting assay from 3054 blood samples from 199 adults and adolescents and 61 children who received efanesoctocog alfa in the aforementioned studies. Body weight and VWF antigen level ranged from 12.5 kg-133 kg and 40 IU/dL-339 IU/dL, respectively. A one-compartment model with linear elimination was used to characterize FVIII activity with an estimated allometric body weight effect on clearance (CL) and volume of central compartment (V) to account for the dependence of CL and V on body size. Baseline VWF, baseline hematocrit, race (White and Asian), hepatitis C virus and human immunodeficiency virus status, and blood types (A, B, O) were tested for statistical significance in the covariate analysis. The final popPK model was used to simulate various dose regimens in a virtual population of adult and adolescent patients generated using baseline body weight distribution from the Phase 1/2a studies and XTEND-1. Results The final popPK model described the FVIII activity over time profile, captured inter-individual variability in FVIII activity, and precisely estimated moderate inter-individual variability in CL and V (Table). Body weight effect allometric exponents showed that absolute CL and V increase with body weight, with overall faster elimination with lower body weight. Asian race was identified as a statistically significant covariate on CL (P<0.001); CL in Asians was 10.4% lower than in non-Asians. Baseline VWF level was not identified as a statistically significant covariate in the final popPK model, consistent with prior studies that demonstrate that the PK of efanesoctocog alfa is VWF-independent. Simulated steady-state FVIII activity over time for efanesoctocog alfa is presented in the Figure. The final popPK model showed that a once-weekly efanesoctocog alfa (50 IU/kg) prophylaxis regimen achieves a steady state Ctrough of >10 IU/dL and the time to 40 IU/dL FVIII activity was 3 to 4 days in the majority of adult and adolescent patients, irrespective of body weight and race. Simulations for perioperative management during major surgery and treatment of major bleeds showed that a loading dose of 50 IU/kg, followed by 30 IU/kg every 3 days in the postoperative period, met the World Federation of Hemophilia guidelines for peak FVIII activity for most adults and adolescents. Similarly, for minor surgeries and treatment of moderate to minor bleeds, a single dose of 50 IU/kg efanesoctocog alfa resulted in peak FVIII activity that met these guidelines. Conclusions A linear one-compartment popPK model was able to adequately characterize FVIII activity in patients with severe hemophilia A. Although CL and V depended on body weight and Asian race was identified as a covariate on CL, body weight and Asian race's limited influence on FVIII exposure was not considered clinically meaningful. PopPK simulations demonstrated that 50 IU/kg once weekly efanesoctocog alfa achieved sustained FVIII activity in the normal to near-normal range (>40 IU/dL) for 3-4 days and >10 IU/dL at Day 7 in most adults and adolescents. PopPK simulations also supported the Phase 3 dose regimens selected for regular prophylaxis, treatment of bleeds, and perioperative management. Study was funded by Sanofi and Sobi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetic Analyses of Ravulizumab on-Body Delivery System for Subcutaneous Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria

Background: The efficacy of ravulizumab (intravenous [IV] formulation administered every 8 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) has been demonstrated in randomized trials (NCT02946463, NCT03056040, NCT03406507, NCT02949128). Studies of IV ravulizumab have established the target therapeutic pharmacokinetic (PK) threshold of 175 μg/mL for complete and sustained terminal complement inhibition (free C5 < 0.5 µg/mL) in patients with PNH and aHUS; maintenance of serum ravulizumab trough concentration (Ctrough) above this threshold ensures clinical efficacy. In study 303 (NCT03748823), the on-body delivery system for subcutaneous (SUBQ) ravulizumab administration (490 mg self-administered weekly) showed PK non-inferiority to IV ravulizumab after 71 days of treatment in adult patients with PNH weighing ≥ 40 to < 100 kg who were clinically stable on prior IV eculizumab treatment (Yenerel et al. HemaSphere 2021;5:e566). In this study, a population PK (popPK) model was developed to characterize ravulizumab PK following IV or SUBQ ravulizumab treatment in patients with PNH, which was then used to generate model-based dosing simulations to support SUBQ and IV ravulizumab posology. Aims: To develop a popPK model and perform simulations to evaluate model-predicted 1) ravulizumab concentrations following IV and SUBQ administration over 1 year of treatment, 2) ravulizumab exposures following SUBQ administration in patients weighing ≥ 100 kg and 3) impact of switching administration route (from IV to SUBQ ravulizumab and vice versa). Methods: A popPK analysis of ravulizumab was performed using data from patients enrolled in three clinical trials (NCT05288829, NCT05396742, NCT03748823). Concentration-time profiles of ravulizumab following IV and SUBQ administration were simultaneously modeled with a 2-compartment model with linear clearance. Ravulizumab absorption following SUBQ administration was modeled using a first-order rate constant of absorption (Ka), bioavailability and lag time. Model-based analyses for repeated measures PK endpoints were conducted using nonlinear mixed effects modeling. The final popPK model accounted for covariates such as body weight, body mass index, disease status and hemoglobin, and was used to simulate steady state concentration profiles following dosing over 1 year, exposure in virtual patients weighing ≥ 100 kg and the impact of a switch in administration route after differing durations of dosing. Results: In total, 2689 blood samples (SUBQ: 1728; IV: 961) were obtained from 178 participants (129 with PNH and 49 without; 115 treated with SUBQ and 63 IV ravulizumab; 46.6% female; aged 18-79 years; body weight 43.5-98.4 kg). The mean (standard deviation) terminal elimination half-life of ravulizumab after SUBQ dosing was 52.4 (9.72) days. The bioavailable fraction of ravulizumab after SUBQ administration was 79.4%. The model-predicted geometric mean ratio (GMR) of SUBQ compared with IV Ctrough on Day 71 and 351 (steady state) were 1.213 and 1.392, respectively (Figure) and comparable to the Day 71 GMR of 1.257 in study 303, indicating the developed popPK model accurately characterized ravulizumab exposure for the ≥ 40 to < 100 kg body weight range in the trial. Simulations predicted that SUBQ ravulizumab Ctrough both remained above the target PK threshold and was non-inferior to ravulizumab IV for body weights ≥ 100 kg. Simulations describing a switch in ravulizumab formulation (IV to SUBQ or SUBQ to IV) show all concentrations remained within our target exposure range regardless of dosing order, after a single dose or after 6 months of dosing. Conclusions: A popPK model was developed and used to support an expanded indication and unrestricted dosing interchangeability between SUBQ and IV ravulizumab. Simulations using the popPK model predicted that switching SUBQ or IV ravulizumab administration route still maintained ravulizumab concentration within the target exposure range supporting treatment flexibility for patients receiving ravulizumab, and that the studied dose regimen maintained ravulizumab concentrations above the PK threshold for patients with body weight ≥ 100 kg. This study illustrates the utility of popPK modeling and simulation to supplement clinical trial results in expanding the target population and dosing options for patients with rare diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population pharmacokinetics analysis of camidanlumab tesirine in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma.

The objective of this analysis was to develop a population pharmacokinetic (PPK) model to characterize camidanlumab tesirine (Cami) pharmacokinetics based on the phase 1 study in relapsed/refractory lymphoma (NCT02432235). An initial PPK model was developed based on a two-compartment model with parallel linear and nonlinear elimination pathways. Pharmacokinetic parameters were evaluated for correlation with potential demographic covariates; significant covariates were retained in the final model. In the final PPK model, baseline weight effects were included on clearance (CL), intercompartmental clearance (Q), and the volumes of distribution in the central (V1) and peripheral (V2) compartments. The baseline soluble CD25 (sCD25) effect was included on CL and maximum velocity of saturable clearance (Vmax); sex effect was included on CL and V1; and ethnicity effect was included on deconjugation clearance (CLdec). For a typical patient, CL and CLdec were 0.516 and 0.21L/day, respectively (tAb elimination half-life: 18.72days); V1 and V2 were 4.41 and 2.67 L, respectively; Vmax was 0.49mg/day; the Michaelis-Menten constant (Km) was 0.409µg/mL; and the first-order rate for decrease of Vmax (KDES) was 0.0197/day. Cami exposure was higher for patients with low baseline sCD25, higher body weight, and females. The final model described the observed data well, estimates of PK parameters were obtained, and covariates with significant effects on Cami exposure were identified. Altogether, this final PPK model provides a robust basis for analysis of Cami exposure-response relationships and further supports identification of the optimal Cami dosing schedule for patients with relapsed/refractory lymphoma.

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7–28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

Population Pharmacokinetic Analysis of Valsartan in Healthy Chinese Subjects.

The study was conducted to establish a population pharmacokinetic (PPK) model of valsartan in Chinese healthy subjects and investigate potential covariate impacts on the pharmacokinetics (PK) parameters. Data from a bioequivalence study with 78 Chinese healthy subjects were retrospectively analyzed to develop a PPK model of valsartan. Phoenix NLME 8.1 was used to build a PPK model and quantify the effects of covariates, such as demographic data and biochemical, on the PK parameters of valsartan. For the healthy Chinese population, valsartan conformed to the two-compartment model with an absorption lag time. In the final PPK model, food affected the absorption rate constant, while aspartate aminotransferase, alanine aminotransferase, and creatinine affected the clearance of the central compartment. The final PPK model was verified to be reproducible, and it can be used to evaluate the PK parameters. This is the first research describing the PPK profile of valsartan in healthy Chinese subjects, and it is expected to provide relevant PK parameters for further study of valsartan.

Population pharmacokinetic-pharmacodynamic analyses of amyloid positron emission tomography and plasma biomarkers for lecanemab in subjects with early Alzheimer's disease.

Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregate species, while demonstrating low affinity for Aβ monomer. This article describes the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by Aβ42/40 ratio and plasma p-tau181 following i.v. administration of lecanemab in subjects with early Alzheimer's disease. Lecanemab PKs were well-characterized with a two-compartment model with first-order elimination. Final PK model contained covariate effects of anti-drug antibody positive status, sex, body weight, and albumin on clearance. The time course of amyloid PET standard uptake ratio (SUVr), plasma Aβ42/40 ratio, and p-tau181 were described using indirect response models with lecanemab exposure as a maximum effect function stimulating the reduction of SUVr, and as a linear function increasing Aβ42/40 ratio and decreasing p-tau181 formation rates. PK/PD simulations show that 10mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aβ42/40 ratio as compared to 10mg/kg monthly dose. Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aβ42/40 ratio and p-tau181 return to baseline levels faster than amyloid. Given the relationship between changes in amyloid PET SUVr and soluble biomarkers, the developed PK/PD models can be used to inform lecanemab dose regimens in future clinical studies.

Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations

Objectives The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. Methods We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. Results The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower C max, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. Conclusions Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower C max and later T max than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Initial sirolimus dosage recommendations for pediatric patients with PIK3CD mutation-related immunodeficiency disease.

Sirolimus is used to treat pediatric patients with PIK3CD mutation-related immunodeficiency disease. However, the initial dosages of sirolimus remain undecided. The present study aims to explore initial dosages in pediatric patients with PIK3CD mutation-related immunodeficiency disease. Pediatric patients with this disease were analyzed using the population pharmacokinetic (PPK) model and the Monte Carlo simulation. Body weight and concomitant use of posaconazole were included in the final PPK model, where, under the same weight, clearances of sirolimus were 1 : 0.238 between children without and children with posaconazole. Without posaconazole, the initial dosages of sirolimus were 0.07, 0.06, 0.05, and 0.04 mg/kg/day for body weights of 10–14, 14–25, 25–50, and 50–60 kg, respectively. With posaconazole, the initial dosages of sirolimus were 0.02 mg/kg/day for body weights of 10–60 kg. This is the first attempt to build a sirolimus PPK model for recommending initial dosages in children with PIK3CD mutation-related immunodeficiency disease, thereby providing a reference for individualized clinical drug administration.

Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms

Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants.

Population pharmacokinetic analysis of etrolizumab in patients with moderately-to-severely active ulcerative colitis.

Etrolizumab is an IgG1‐humanized monoclonal antibody that specifically targets the β7 subunit of α4β7 and α4Eβ7 integrins, and it has been evaluated for the treatment of moderately‐to‐severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was performed to characterize etrolizumab PK properties in patients with moderately‐to‐severely active UC and evaluate covariate impacts on exposure. The population PK model was developed based on etrolizumab serum concentrations from patients with moderately‐to‐severely active UC enrolled in six studies (one phase I, one phase II, and four phase III) and validated using another phase III clinical trial. Stepwise covariate modeling was used to evaluate the impact of 23 prespecified covariates. Etrolizumab PK was best described by a two‐compartment model with first‐order absorption, with clearance decreasing over time. Population typical values were 0.260 L/day for clearance (CL) during the first dosing internal, 2.61 L for central volume, 71.2% for bioavailability, and 0.193/day for absorption rate. CL reduced over the study duration, the typical maximum reduction was 26% with an onset half‐life of 4.8 weeks. Consequently, the predicted mean terminal half‐life was shorter after a single dose (13.0 days) compared to that at steady‐state (17.1 days). Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Final population PK model well characterized the PK properties of etrolizumab in patients with moderately‐to‐severely active UC and identified influential covariate effects.

Daptomycin Population Pharmacokinetics in Patients Affected by Severe Gram-Positive Infections: An Update.

Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during a routine therapeutic drug monitoring protocol. Model building and validation were performed using NONMEM 7.2 (ICON plc), Xpose4 and Perl-speaks-to-NONMEM. The final pop-PK model was a one-compartment first-order elimination model, with a 2.7% IIV for drug clearance (Cl), influence of creatinine clearance on drug clearance and of sex on distribution volume. After model validation, we simulated 10,000 patients with the Monte-Carlo method to predict the efficacy and tolerability of different daptomycin daily dosages. For the most common 6 mg/kg daily dose, the simulated probability of overcoming the toxic minimum concentration (24.3 mg/L) was 14.8% and the efficacy (expressed as a cumulative fraction of response) against methicillin-resistant S. aureus, S. pneumoniae and E. faecium was 95.77%, 99.99% and 68%, respectively. According to the model-informed precision dosing paradigm, pharmacokinetic models such as ours could help clinicians to perform patient-tailored antimicrobial dosing and maximize the odds of therapy success without neglecting toxicity risks.

Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients

PurposeA population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model.MethodsBody composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis.ResultsIn 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = − 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated.ConclusionThe phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual’s tacrolimus dose requirement after transplantation.

Timing of re-dosing based on population pharmacokinetic-pharmacodynamics target attainment analysis of cefmetazole in subjects undergoing lower gastrointestinal surgery

IntroductionThis study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval. MethodsSerum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae ResultsThe final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr ≧ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr ≧ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h. ConclusionsWe evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function.

Real-World Experience with First FDA-Approved Oral Testosterone Undecanoate Formulation

ABSTRACT Introduction The diagnosis of hypogonadism (HG) in men requires both consistently low testosterone (T) levels and signs and symptoms of T deficiency. Management of HG with T replacement therapy (TRT) aims to improve both low serum T levels and patients’ symptomatic complaints. The first oral softgel formulation of testosterone undecanoate (TU) was recently approved by FDA (JATENZO®) for TRT in men with specific hypogonadal conditions and is available in 3 capsule strengths and 5 dosage combinations for necessary dose adjustments. However, dose titration may not be necessary in many patients treated with this new oral TU formulation given the wide eugonadal range. Objective Assess the ability of any given daily dosage of oral TU to restore T to eugonadal levels without dose adjustment at steady state (Css); and determine real-world dose titration experience of patients treated with oral TU. Methods Pharmacokinetic (PK) simulations were performed using a robust population PK model developed for T in 474 hypogonadal men who were treated with oral TU in prior PK studies. The model consisted of a 1-compartment model with absorption lag time and an allometric function on key allometric parameters to account for differences in body weight. This final population PK model was coded in Trial Simulator v2.3.0.6 software. T levels were simulated following oral TU BID dosing on Day 55 (i.e., at steady state) with no dose adjustments. Average T concentrations (Cavg) were derived from multiple serial blood samples collected over 24 hrs for oral TU doses of 237, 316, and 396 mg TU, BID (without dose modification). The percent of subjects with T levels within the eugonadal range (serum Cavg between 304 ng/dL-1030 ng/dL) at each of these TU dose levels was calculated. Prescription data was also accessed in the Symphony PatientSource Patient Transactional Dataset to evaluate the frequency of real-world dose titration. Results The percentage of subjects with Css T Cavg within the eugonadal range for 237, 316, and 396 mg TU, BID were 61%, 74% and 74%, respectively. These corresponded to mean [5%, 95% CI] serum T levels (ng/dL) of 398 [389, 406], 560 [549, 572] and 728 [715, 741] ng/dL, respectively. Early assessment of real-world prescribing data for JATENZO indicated 35% of patients underwent dose titration by month 5. Conclusions Simulated daily BID dosing of oral TU without dose adjustment yielded eugonadal T levels in most subjects at all 3 dose levels examined. These data are consistent with initial early real-world experience with oral TU that indicates dose titration has not been required in most patients. However, because the desired outcome of TRT therapy focuses on both T Cavg and symptomatic response, this oral TU formulation enables necessary dose adjustment when needed. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics, Inc.

Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms.

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL2/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL2/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide’s cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient’s genotypes into account might become possible.

Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis.

Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed model to establish a model-informed precision dosing (MIPD) algorithm enabling safe and efficacious dosing in patients with multidrug- and extensively drug-resistant tuberculosis. Routine hospital therapeutic drug monitoring data, collected from 70 tuberculosis patients receiving linezolid, was used for model development. Efficacy and safety targets for MIPD were the ratio of unbound area under the concentration versus time curve between 0 and 24 h over minimal inhibitory concentration (fAUC0–24h/MIC) above 119 and unbound plasma trough concentration (fCmin) below 1.38 mg/L, respectively. Model building was performed in NONMEM 7.4.3. The final population pharmacokinetic model consisted of a one-compartment model with transit absorption and concentration- and time-dependent auto-inhibition of elimination. A flat dose of 600 mg once daily was appropriate in 67.2% of the simulated patients from an efficacy and safety perspective. Using the here developed MIPD algorithm, the proportion of patients reaching the efficacy and safety target increased to 81.5% and 88.2% using information from two and three pharmacokinetic sampling occasions, respectively. This work proposes an MIPD approach for linezolid and suggests using three sampling occasions to derive an individualized dose that results in adequate efficacy and fewer safety concerns compared to flat dosing.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants.

ObjectivesThe objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1–3 months old.MethodsPPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold).ResultsThirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26–56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min.ConclusionThis PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1–0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.