Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients—nonlinear mixed effects modelling approach

Purpose

The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach.

Methods

The study included 53 patients (age range 3–35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools.

Results

The final LTG population model included the effects of concomitant drugs and patient’s weight (WT) which stratified the population into three groups: ≤25 kg, >25 to <60 kg and ≥60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing ≤25 kg, >25 to <60 kg or ≥60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ.

Conclusion

The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring.     

Effects of mood stabilizers on marble-burying behavior in mice

Rationale

Obsessive–compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD.

Objectives

In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior.

Methods

The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated.

Results

Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA_A receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA_B receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA_A receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg).

Conclusions

These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA_A receptor-dependent mechanism.     

Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China

Objective

The pharmacokinetics of lamotrigine (LTG) varies significantly among individuals and particularly among different ethnic groups. This is in part due to the presence of genetic polymorphisms affecting genes that metabolize LTG. UGT1A4 is a major metabolizing enzyme of LTG. The aim of this study was to investigate the effect of two UGT1A4 gene polymorphisms, UGT1A4 (70C?>?A) and UGT1A4 (142 T?>?G), on the levels and efficacy of LTG in Han Chinese patients with epilepsy.

Methods

The study cohort comprised 106 Han Chinese patients patients with epilepsy who were receiving LTG monotherapy. Blood samples were taken and LTG levels measured. The presence of UGT1A4 (70C?>?A) and UGT1A4 (142 T?>?G) was determined. The therapeutic efficacy of LTG at the 1-year time-point was assessed.

Results

All patients were homozygous for the CC genotype of UGT1A4 (70C?>?A), while the distribution of UGT1A4 (142 T?>?G) varied among patients. Two patients had a single nucleotide deletion at position 127 (UGT1A4 127delA). To evaluate the effect of the UGT1A4 (142 T?>?G) polymorphism on LTG pharmacokinetics, patients were divided into two groups. Group A included patients with the 142TG or 142GG polymorphism and Group B patients had the 142TT polymorphism. The normalized blood concentration and the efficacy of LTG were higher in Group B patients than in Group A patients (P?<?0.05). The two patients with UGT1A4 127delA genotype had extremely high blood levels of LTG, and treatment was discontinued in one of these patients due to a severe LTG-associated rash.

Conclusion

Patients with the UGT1A4 142TT polymorphism had a higher blood LTG concentration and better therapeutic efficacy, suggesting that this polymorphism influences LTG activity. The UGT1A4 127delA polymorphism significantly affected LTG levels and increased one of our patient's susceptibility to LTG-related adverse events.     

Population pharmacokinetic analysis of sorafenib in patients with solid tumours

AIMS

To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.

METHODS

PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.

RESULTS

A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h⁻¹ (3.6–22.3 l h⁻¹), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.

CONCLUSIONS

Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.     

Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors

Purpose

To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.

Methods

Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m². Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®.

Results

PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. V_encap in male patients is 1.5-fold higher compared with female patients.

Conclusions

The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.     

Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

Purpose

Knowledge of the pharmacokinetics (PK) of plasma-derived factor IX (FIX) is still inadequate, with conflicting findings on its elimination half-life and as yet no analysis of the variance in PK between and within individuals. The aim of the study was thus to characterize the PK of plasma-derived FIX, including estimates of variance between and within patients, in adult patients and to predict the variation between individuals in dose requirement to produce a target trough level during regular prophylaxis.

Methods

Plasma FIX versus time data were compiled from four published and one unpublished PK study involving a total of 26 adult patients with severe haemophilia B. The number of PK assessments per patient varied between one and eight, yielding in total 893 measured FIX levels from 80 study occasions. A population PK model was developed to describe the whole dataset. Parameter values from the model were used to calculate the dose requirement to maintain a trough level of 1% of normal FIX activity in each patient.

Results

The disposition of FIX was well described by a three-compartment PK model. The median elimination half-life was 31 h, and the variation between individuals was modest both in PK and in dose requirement during twice-weekly prophylaxis.

Conclusion

With twice weekly dosing, the need for PK-based dose tailoring of FIX in adult patients appears to be limited. However, monitoring FIX levels should be considered in children, in patients who do not respond satisfactorily to standard dosing, and if treatment is switched from plasma-derived to recombinant FIX.     

Population pharmacokinetic–pharmacodynamic analysis for eribulin mesilate-associated neutropenia

Aims

Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic–pharmacodynamic model for eribulin-associated neutropenia.

Methods

A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.

Results

Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC₀) was estimated to be 4.03 × 10⁹ neutrophils l⁻¹ [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l⁻¹ (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.

Conclusions

The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.     

Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation

Purposes

Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation.

Methods

Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients’ demographics, biochemical test results and physiological characteristics.

Results

The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h^-1 and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution.

Conclusions

We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM.     

Anti-Neuropilin-1 (MNRP1685A): Unexpected Pharmacokinetic Differences Across Species, from Preclinical Models to Humans

Purpose

To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances.

Methods

Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species.

Results

MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non-specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5?ml/day/kg), but not in monkeys (3.22?ml/day/kg).

Conclusions

Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms.     

Pharmacokinetic and Pharmacodynamic Modeling of Opioid-Induced Gastrointestinal Side Effects in Patients Receiving Tapentadol IR and Oxycodone IR

Purpose

To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.

Methods

The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.

Results

Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3?C4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.

Conclusions

This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.     

Leveraging Physiological Data from Literature into a Pharmacokinetic Model to Support Informative Clinical Study Design in Pregnant Women

Purpose

Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy.

Methods

Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models.

Results

The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was succesfully developed, with parameters expected with good precision (RSE?Conclusion A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable.     

Prediction of the tacrolimus population pharmacokinetic parameters according to CYP3A5 genotype and clinical factors using NONMEM in adult kidney transplant recipients

Purpose

Tacrolimus is a commonly used immunosuppressant in solid organ transplantation recipients, but it is characterized by a narrow therapeutic range and large inter-individual variability. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene encoding P-glycoprotein (ABCB1), on the PK parameters in adult Korean kidney transplant recipients.

Methods

Clinical data were collected retrospectively for 400 days after the initiation of a tacrolimus-based immunosuppression therapy. Data from 2,788 trough blood samples obtained from 80 subjects were used to perform a population PK analysis with a nonlinear mixed-effect model (NONMEM).

Results

The estimated population mean values of clearance (CL/F) and volume of distribution (V/F) were 22.9 L/h and 716 L, respectively, and the k _a was fixed to 4.5 h^-1. The CYP3A5 genotype, hematocrit level, and post-operative days were identified as the main covariates that influence CL/F, and body weight was found to have a significant effect on V/F. Other covariates, including ABCB1 genotype, corticosteroid dosage, sex, and other clinical data, did not contribute to the pharmacokinetics of tacrolimus.

Conclusions

This tacrolimus population PK model will be a valuable tool in developing rational guidelines and provides a basis for individualized therapy after kidney transplantation in clinical settings of Korea.     

Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

Purpose

Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders.

Methods

Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n?=?107) and in treatment-naive patients (n?=?35) and interferon-null responders (n?=?24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference).

Results

The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56–0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39–0.53) compared to volunteers. The mean area under the concentration–time curve (AUC_inf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.

Conclusions

The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.     

Marked Differences in the Effect of Antiepileptic and Cytostatic Drugs on the Functionality of P-Glycoprotein in Human and Rat Brain Capillary Endothelial Cell Lines

Purpose

The expression of P-glycoprotein (Pgp) is increased in brain capillary endothelial cells (BCECs) of patients with pharmacoresistant epilepsy. This may restrict the penetration of antiepileptic drugs (AEDs) into the brain. However, the mechanisms underlying increased Pgp expression in epilepsy patients are not known. One possibility is that AEDs induce the expression and functionality of Pgp in BCECs. Several older AEDs that induce human cytochrome P450 enzymes also induce Pgp in hepatocytes and enterocytes, but whether this extends to Pgp at the human BBB and to newer AEDs is not known.

Methods

This prompted us to study the effects of various old and new AEDs on Pgp functionality in the human BCEC line, hCMEC/D3, using the rhodamine 123 (Rho123) efflux assay. For comparison, experiments were performed in two rat BCEC lines, RBE4 and GPNT, and primary cultures of rat and pig BCECs. Furthermore, known Pgp inducers, such as dexamethasone and several cytostatic drugs, were included in our experiments.

Results

Under control conditions, GPNT cells exhibited the highest and RBE4 the lowest Pgp expression and Rho123 efflux, while intermediate values were determined in hCMEC/D3. Known Pgp inducers increased Rho123 efflux in all cell lines, but marked inter-cell line differences in effect size were observed. Of the various AEDs examined, only carbamazepine (100 μM) moderately increased Pgp functionality in hCMEC/D3, while valproate (300 μM) inhibited Pgp.

Conclusions

These data do not indicate that treatment with AEDs causes a clinically relevant induction in Pgp functionality in BCECs that form the BBB.     

Predicting Nonlinear Pharmacokinetics of Omeprazole Enantiomers and Racemic Drug Using Physiologically Based Pharmacokinetic Modeling and Simulation: Application to Predict Drug/Genetic Interactions

Purpose

The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.

Methods

By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.

Results

The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.

Conclusions

PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole.     

Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor

Purpose

For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4R??, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response.

Methods

Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients.

Results

The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0?mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03?L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured.

Conclusion

The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.     

Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation

Purpose

To build a population pharmacokinetic (PK) model of cyclophosphamide (CY) and its metabolite, 4-hydroxycyclophosphamide (HCY), in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and to identify covariates, including genetic polymorphisms, which affect CY and HCY PK parameters.

Method

The study cohort comprised 21 patients undergoing HSCT who received CY intravenously between 2009 and 2011. Clinical characteristics and CY and HCY concentration data were collected for all patients, and ABCB1, ABCC2, GSTA1, GSTM1, GSTP1, GSTT1, CYP2B6, CYP2C19, and CYP3A5 genotyping was performed. A hypothetical enzyme compartment was conducted using the NONMEM program.

Results

A population PK analysis showed that the ABCC2 1249 genotype and aspartate aminotransferase levels significantly affected non-induced clearance (CL _UI) and induced clearance (CL _I) of CY, respectively. The final estimate of the mean CL _UI and CL _I of CY was 15.5 and 0.683 L/h, respectively, and the mean volume of distribution (V ₁) of CY was 88.0 L. The inter-individual variability for CL _UI, CL _I, and V ₁ of CY was 52.8, 200, and 18.0 %, respectively. Additionally, the CL _UI of CY was significantly decreased to approximately 51 % in patients with the 1249 GA heterozygous genotype compared to those with the 1249 GG wild-type genotype (p?<?0.05). There were only three heterozygous GA variants of ABCC2 1249 in the study patients.

Conclusions

The population PK model developed in this study implies an influence of genetic factors on the clearance of CY. Clearance was moderately reduced in patients with the ABCC2 1249GA heterozygous genotype.     

Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease

Purpose

To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation.

Methods

This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6?weeks postdose.

Results

Mean vorapaxar bioavailability (based on area under the curve of plasma vorapaxar concentration over time) was identical in the two subject groups; the ESRD/healthy geometric mean ratio (GMR, expressed in percent) was 98. Mean maximum observed plasma concentration (77.4–98.2?ng/mL) was numerically lower in patients with ESRD compared with matched controls (GMR?=?76; 90% confidence interval?=?48 to 118). Median time of maximum observed plasma concentration was 2?h in both subject groups. The observed means for elimination half-life were 186 and 231?h in the ESRD and control groups, respectively. Inhibition of platelet aggregation was similar in the two groups. Four out of 15 (27%) subjects reported adverse events, all of which were characterized by the investigator as mild and unrelated to treatment.

Conclusions

ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.     

Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment

Purpose

Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.

Methods

This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.

Results

DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.

Conclusions

The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.     

Practical recommendations for population PK studies with sampling time errors

Purpose

Population pharmacokinetic (PK) data collected from routine clinical practice offers a rich source of valuable information. However, in observational population PK data, accurate time information for blood samples is often missing, resulting in measurement errors (ME) in the sampling time variable. The goal of this study was to investigate the effects on model parameters when a scheduled time is used instead of the actual blood sampling time, and to propose ME correction methods.

Methods

Simulation studies were conducted based on two major factors: the curvature in PK profiles and the size of ME. As ME correction methods, transform both sides (TBS) models were developed with application of Box-Cox power transformation and Taylor expansion. The TBS models were compared to a conventional population PK model using simulations.

Results

The most important determinant of bias due to time ME was the degree of curvature (nonlinearity) in PK profiles; the smaller the curvature around sampling times, the smaller the associated bias. The second important determinant was the magnitude of ME; the larger the ME, the larger the bias. The proposed TBS models performed better than a conventional population PK modeling when curvature and ME were substantial.

Conclusions

Time ME in sampling time can lead to bias on the parameter estimators. The following practical recommendations are provided: 1) when the curvature of PK profiles is small, conventional population PK modeling is robust to even large ME; and 2) when the curvature is moderate or large, the proposed methodology reduces bias in parameter estimates.