Publications by authors named "Richard C Brundage"

69 Publications

A Pharmacokinetic Simulation Study to Assess the Performance of a Sparse Blood Sampling Approach to Quantify Early Drug Exposure.

Clin Transl Sci 2021 Mar 20. Epub 2021 Mar 20.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, Minneapolis, MN, USA.

Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic information for estimating early exposure. The performance of a modeling approach was compared to a non-compartmental analysis (NCA). A simulation study was performed using literature-based models for phenytoin (PHT), levetiracetam (LEV) and valproic acid (VPA). These models were used to simulate rich concentration-time profiles from 0-2 hours. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area-under-the-curve 0-2 hours (pAUC). From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual PopPK pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPE) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ± 20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81, 92 and 88%were significantly higher than the 72, 80 and 67% using the NCA approach (p<0.05; Mann-Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a population pharmacokinetics approach. It can be applied to other settings in which early exposures are of interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.13004DOI Listing
March 2021

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus.

J Clin Pharmacol 2020 Dec 17. Epub 2020 Dec 17.

Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1801DOI Listing
December 2020

Hydrocortisone suspension formulations are not necessarily the same in the treatment of children with congenital adrenal hyperplasia.

Eur J Endocrinol 2020 Dec;183(6):L27-L28

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-20-0938DOI Listing
December 2020

Manipulation of Hydrocortisone Tablets Leads to Iatrogenic Cushing Syndrome in a 6-Year-Old Girl With CAH.

J Endocr Soc 2020 Aug 5;4(8):bvaa091. Epub 2020 Jul 5.

Department of Pediatrics, Division of Endocrinology, University of Minnesota, Minneapolis, Minnesota.

Currently there are no commercially available hydrocortisone formulations for the treatment of children with congenital adrenal hyperplasia (CAH) that allow for smaller doses (0.1-1.25 mg) and incremental adjustments needed to control excess androgen production and avoid the negative effects of overtreatment. This lack of availability has led physicians to recommend dividing hydrocortisone 5-mg tablets into 4 to 6 pieces, compounding capsules or hydrocortisone suspension, or crushing 5- or 10-mg tablets in 5 or 10 mL of water. We report a case of iatrogenic Cushing syndrome in a 6-year 11-month-old girl with salt-wasting CAH treated with hydrocortisone tablets that were administered after crushing and dispersing into water to obtain the prescribed dose. She presented with poor growth, increasing body mass index (BMI), excess downy hair, round facies, and gastric ulcers. Her hydrocortisone dose was 8.1 mg/m/day. Results for all adrenal steroid concentrations were undetectable at 8 am, 12 hours after her last dose. The year prior to presentation her parents began dissolving 10 mg of hydrocortisone in 10 mL of water and using this preparation over the course of 24 hours, which coincided with rapid increase of BMI. We switched her to a pharmacy-compounded alcohol-free hydrocortisone suspension with total daily doses ranging from 6.5 to 8.2 mg/m/day, which resulted in resolution of her cushingoid features, a decrease in BMI, and catch-up growth. Our case highlights that manipulation of hydrocortisone tablets by parents can result in great variability in dosing and the need for commercially available pediatric formulations allowing for smaller dosing required in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvaa091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417883PMC
August 2020

An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.

Br J Clin Pharmacol 2021 Mar 26;87(3):1098-1110. Epub 2020 Jul 26.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Aims: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH).

Methods: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an I model.

Results: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively.

Conclusion: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14470DOI Listing
March 2021

Individualized Absorption Models in Population Pharmacokinetic Analyses.

CPT Pharmacometrics Syst Pharmacol 2020 06 21;9(6):307-309. Epub 2020 May 21.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/psp4.12513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306615PMC
June 2020

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis.

AAPS J 2020 05 19;22(4):73. Epub 2020 May 19.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline C and AUC increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while T and t did not change with dose. Following multiple oral doses, C and AUC increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, T, and t remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal E function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12248-020-00455-yDOI Listing
May 2020

Physiologically-Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues.

Clin Pharmacol Ther 2020 07 1;108(1):136-144. Epub 2020 Apr 1.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

Significant in vitro and in vivo evidence supports the potential use of sertraline as an anticancer and antimicrobial agent. Yet, it is unknown whether effective sertraline concentrations are clinically achieved at therapeutic doses. The study objectives were to develop a physiologically-based pharmacokinetic (PBPK) model of sertraline and estimate the probability of achieving effective concentrations in various human tissues. A generic PBPK model consisting of perfusion-limited compartments representing the body organs linked together by blood flows and incorporated with clearance, tissue distribution, and absorption models was implemented in R using the mrgsolve package. Sertraline clearance and volume of distribution were first optimized from i.v. plasma concentration data then absorption and bioavailability were optimized from oral data. Predicted unbound sertraline concentrations at steady-state in human tissues did not reach concentrations determined in vitro, indicating therapeutic doses of sertraline are unlikely to produce concentrations required for anticancer and antimicrobial activities in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.1824DOI Listing
July 2020

Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis.

J Pharmacokinet Pharmacodyn 2019 12 4;46(6):565-576. Epub 2019 Oct 4.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0.7-1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound sertraline concentrations is unlikely to reach MIC concentrations in the brain. Study findings also recommend against the use of higher doses of sertraline, especially those greater than the maximum FDA-approved daily dose (200 mg/day), since they unlikely provide any additional benefits and come with greater costs and risk of adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10928-019-09657-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004416PMC
December 2019

Precision medicine in adult and pediatric obesity: a clinical perspective.

Ther Adv Endocrinol Metab 2019 27;10:2042018819863022. Epub 2019 Jul 27.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

It remains largely unknown as to why some individuals experience substantial weight loss with obesity interventions, while others receiving these same interventions do not. Person-specific characteristics likely play a significant role in this heterogeneity in treatment response. The practice of precision medicine accounts for an individual's genes, environment, and lifestyle when deciding upon treatment type and intensity in order to optimize benefit and minimize risk. In this review, we first discuss biopsychosocial determinants of obesity, as understanding the complexity of this disease is necessary for appreciating how difficult it is to develop individualized treatment plans. Next, we present literature on person-specific characteristics associated with, and predictive of, weight loss response to various obesity treatments including lifestyle modification, pharmacotherapy, metabolic and bariatric surgery, and medical devices. Finally, we discuss important gaps in our understanding of the causes of obesity in relation to the suboptimal treatment outcomes in certain patients, and offer solutions that may lead to the development of more effective and targeted obesity therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2042018819863022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661805PMC
July 2019

Comparative Evaluation of Median Versus Youden Index Dichotomization Methods: Exposure-Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite.

Eur J Drug Metab Pharmacokinet 2019 Oct;44(5):629-638

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Background And Objectives: Dichotomization of pharmacokinetic exposure measures in exposure-response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods.

Methods: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure-response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia.

Results: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure-response associations when considering either the Youden index-based or the median-based dichotomization methods.

Conclusion: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13318-019-00550-2DOI Listing
October 2019

A Gallbladder-Based Enterohepatic Circulation Model for Pharmacokinetic Studies.

Eur J Drug Metab Pharmacokinet 2019 Aug;44(4):493-504

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Background And Objectives: Strategies for modeling the enterohepatic circulation (EHC) process reported in the literature vary; however, gallbladder-based models currently provide the best physiological representation of the process. Regardless, the addition of a gallbladder to the model does not fully depict the physiology of EHC. A more physiological gallbladder-based EHC model is needed. This model should take into account a physiological representation of the bile secretion, gallbladder filling and emptying, the duration of gallbladder emptying, and irregular mealtimes. Considering all of these factors, the objectives of the present analysis were to propose a gallbladder-based EHC model and then to use that model to perform sensitivity analyses evaluating the effect of the extent of EHC on the pharmacokinetic profile and noncompartmental analysis (NCA) calculations.

Methods: A gallbladder-based model that describes the EHC process was developed and used to perform determinant simulations assuming various degrees of EHC. Next, these simulations were compared to evaluate the effect of the EHC on the pharmacokinetic profiles of orally administered drugs. The influence of the EHC process on the NCA calculations was determined while assuming two sampling schemes that differed in the times at which sampling was performed in relation to meal times.

Results: The presence of EHC results in nonlinearity in the system and changes the pharmacokinetic profile, affecting the maximum concentration (C), time to C (T), and half-life estimates. Comparison of the results obtained using the two sampling schemes for a drug undergoing various degrees of EHC demonstrated a significant influence of the selected sampling times on the NCA estimations. Bias in the NCA calculations was also dependent on the sampling times used.

Conclusion: Caution should be taken when designing clinical studies for drugs that undergo EHC. It may be essential to consider the timing of meals when planning pharmacokinetic studies and defining sampling times. The period over which samples are taken needs to be extended as compared to that traditionally used with other drugs. Future studies that attempt to identify the best sampling strategies in the presence of EHC are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13318-018-0535-1DOI Listing
August 2019

Iron supplements in nursing home patients associated with reduced carbamazepine absorption.

Epilepsy Res 2018 11;147:115-118

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States. Electronic address:

Persons in nursing homes receive a number of medications that may interfere with the pharmacokinetics of carbamazepine (CBZ). The aim of our study was to determine factors that may affect the pharmacokinetics of CBZ in elderly nursing home patients.

Methods: CBZ concentration data collected from 60 nursing homes across the US were evaluated. Inclusion criteria included residency in a nursing home for at least 2 months, age 65 years or older, a stable dosing regimen of CBZ for at least 4 weeks (considered steady state), available CBZ concentration, and complete information regarding all co-medications. Using a nonlinear mixed-effects model, the data were adequately described by a one-compartment model with first-order absorption and elimination. Goodness-of-fit plots, plausibility of parameter estimates, visual predictive check and nonparametric bootstrap were used to evaluate the models.

Main Findings: The final data set consisted of 345 CBZ concentrations from 99 subjects (38 males, 61 females). The population estimate of apparent clearance (CL/F) for a 70-kg person was 3.69 L/hr (RSE 6.9%). Residents were receiving either immediate (93.9%) or extended release (6.1%) formulation of CBZ and the K of each formulation was fixed to literature values. Age, sex, and co-medications had no effect on CL/F and apparent volume of distribution. Iron supplementation, which was taken by 16% of the residents, resulted in a 33% decrease in bioavailability (p < 0.001). No other medications were found to have an effect.

Conclusions: Results from this pharmacokinetic study indicate that use of iron supplementation is associated with a reduction in absorption of CBZ and may need to be considered when dosing CBZ in patients taking iron supplementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2018.07.015DOI Listing
November 2018

Lamotrigine pharmacokinetics following oral and stable-labeled intravenous administration in young and elderly adult epilepsy patients: Effect of age.

Epilepsia 2018 09 12;59(9):1718-1726. Epub 2018 Aug 12.

Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

Objective: The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability.

Methods: Patients (>18 years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3).

Results: Twenty-eight patients representing 16 young (18-48 years old) and 12 elderly (63-87 years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70-kg patient).

Significance: Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.14519DOI Listing
September 2018

Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients.

Antimicrob Agents Chemother 2018 04 27;62(4). Epub 2018 Mar 27.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

We performed pharmacokinetic-pharmacodynamic (PK-PD) and simulation analyses to evaluate a standard amikacin dose of 15 mg/kg once daily in children with cancer and to determine an optimal dosing strategy. A population pharmacokinetic model was developed from clinical data collected in 34 pediatric patients and used in a simulation study to predict the population probability of various dosing regimens to achieve accepted safety (steady-state unbound trough plasma concentration [] of <10 mg/liter)- and efficacy (free, unbound plasma concentration-to-MIC ratio [/MIC] of ≥8)-linked targets. In addition, an adaptive resistance PD (ARPD) model of was built based on literature time-kill curve data and linked to the PK model to perform PK-ARPD simulations and compare results with those of the probability approach. Using the probability approach, an amikacin dose of 60 mg/kg administered once daily is expected to achieve the target /MIC in 80% of pediatric patients weighing 8 to 70 kg with a 97.5% probability, and almost all patients were predicted to have of <10 mg/liter. However, PK-ARPD simulation predicted that 60 mg/kg/day is unlikely to suppress bacterial resistance with repeated dosing. Furthermore, PK-ARPD simulation suggested that amikacin at 90 mg/kg, given in two divided doses (45 mg/kg twice a day), is expected to hit safety and efficacy targets and is associated with a lower rate of bacterial resistance. The disagreement between the two methods is due to the inability of the probability approach to predict development of drug resistance with repeated dosing. This originates from the use of PK-PD indices based on the MIC that neglects measurement errors, ignores the time course dynamic nature of bacterial growth and killing, and incorrectly assumes the MIC to be constant during treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01781-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913936PMC
April 2018

Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure.

J Clin Pharmacol 2018 05 12;58(5):628-639. Epub 2018 Jan 12.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions. The aim of this study was i) to develop an integrated model of MPA (total and unbound) and its metabolites (MPAG and acyl-MPAG) in kidney recipients, where this model provides a more physiological representation of EHC process, and ii) to evaluate the effect of donor and recipient clinical covariates and genotypes on MPA disposition. A five-compartment model with first-order input into an unbound MPA compartment connected to the MPAG, acyl-MPAG, and gallbladder compartment best fit the data. To represent the EHC process, the model was built based on the physiological concepts related to the hepatobiliary system and the gallbladder filling and emptying processes. The effect of cyclosporine versus tacrolimus on clearance of unbound MPA was included in the base model. Covariate analysis showed creatinine clearance to be significant on oral clearance of unbound MPA. The hepatic nuclear factor 1 alpha (HNF1A) genetic single nucleotide polymorphism (SNP) (rs2393791) in the recipient significantly affected the fraction of enterohepatically-circulated drug. Oral clearance of MPAG was affected by recipient IMPDH1 SNP (rs2288553), diabetes at the time of transplant, and donor sex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.1064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910266PMC
May 2018

Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients.

AAPS J 2017 03 9;19(2):551-556. Epub 2017 Jan 9.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Room 463, 717 Delaware St., SE, Minneapolis, Minnesota, 55414, USA.

Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12248-016-0022-zDOI Listing
March 2017

Prospective studies of infectious mononucleosis in university students.

Clin Transl Immunology 2016 Aug 12;5(8):e94. Epub 2016 Aug 12.

Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.

We performed an intensive prospective study designed to obtain as much data as possible on the incubation and early illness periods of primary Epstein-Barr virus (EBV) infection. Undergraduate students who lacked EBV antibody and oral EBV DNA (EBV-naive) were seen every 2 weeks during their freshman year. Clinical and behavioral data, oral washes and venous blood were obtained. EBV antibodies were quantified by enzyme immunoassay and viral loads by PCR. During a median 8 months of observation, 14/85 subjects experienced primary EBV infections (24 cases/100 person-years). The only significant risk factor for acquisition of EBV infection was deep kissing (P=0.02). Eleven subjects had infectious mononucleosis with a median duration of 21 days. Two subjects were hospitalized. Infections were initially identified in 12 subjects by finding EBV DNA in oral cells before onset of symptoms and in 2 subjects by symptom reporting. EBV DNA and viral capsid antigen (VCA) IgM and gp350 IgG antibodies were present in the blood before onset of illness. To provide a more robust evaluation of primary EBV infection in undergraduate university students, we combined data on risk factors and antibody responses from this and an earlier study that used the exact same clinical and laboratory methods. The observation that the only significant risk factor for acquisition of EBV infection was deep kissing was confirmed. Most importantly, higher amounts of gp350 antibody correlated significantly with a lower severity of infectious mononucleosis (P<0.0001), which strengthens the rationale for a gp350-based prophylactic EBV vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/cti.2016.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007628PMC
August 2016

A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: Treating adrenoleukodystrophy with Lorenzo's oil.

J Biopharm Stat 2016 22;26(6):1025-1039. Epub 2016 Aug 22.

a Division of Biostatistics , School of Public Health, University of Minnesota , Minneapolis , Minnesota , USA.

X-linked adrenoleukodystrophy (X-ALD) is a rare, progressive, and typically fatal neurodegenerative disease. Lorenzo's oil (LO) is one of the few X-ALD treatments available, but little has been done to establish its clinical efficacy or indications for its use. In this article, we analyze data on 116 male asymptomatic pediatric patients who were administered LO. We offer a hierarchical Bayesian statistical approach to understand LO pharmacokinetics (PK) and pharmacodynamics (PD) resulting from an accumulation of very long-chain fatty acids. We experiment with individual- and observational-level errors and various choices of prior distributions and deal with the limitation of having just one observation per administration of the drug, as opposed to the more usual multiple observations per administration. We link LO dose to the plasma erucic acid concentrations by PK modeling, and then link this concentration to a biomarker (C26, a very long-chain fatty acid) by PD modeling. Next, we design a Bayesian Phase IIa study to estimate precisely what improvements in the biomarker can arise from various LO doses while simultaneously modeling a binary toxicity endpoint. Our Bayesian adaptive algorithm emerges as reasonably robust and efficient while still retaining good classical (frequentist) operating characteristics. Future work looks toward using the results of this trial to design a Phase III study linking LO dose to actual improvements in health status, as measured by the appearance of brain lesions observed via magnetic resonance imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10543406.2016.1226326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393457PMC
November 2017

CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites.

J Clin Pharmacol 2017 03 22;57(3):382-393. Epub 2016 Sep 22.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.

Multiple factors can impact warfarin therapy, including genetic variations in the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild-type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S-enantiomer of the racemic anticoagulant warfarin, may impact warfarin-drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R- and S-warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10-mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4). Plasma clearance of S-warfarin, but not R-warfarin, decreased multiexponentially and in a CYP2C9 gene-dependent manner: 56%, 70%, and 75% for CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes, respectively, compared with CYP2C9*1/*1, resulting in pronounced differences in the S:R ratio that identified warfarin-sensitive genotypes. CYP2C9 was the primary P450 enzyme contributing to S-warfarin metabolism and a minor contributor to R-warfarin metabolism. In the presence of a defective CYP2C9 allele, switching of warfarin metabolism to other oxidative pathways and P450 enzymes for the metabolic elimination of S-warfarin was not observed. The 10-hydroxywarfarin metabolites, whose detailed pharmacokinetics are reported for the first time, exhibited a prolonged half-life with no evidence of renal excretion and displayed elimination rate-limited kinetics. Understanding the impact of CYP2C9 genetics on warfarin pharmacokinetics lays the foundation for future genotype-dependent warfarin-drug interaction studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.813DOI Listing
March 2017

Epstein-Barr virus dynamics in asymptomatic immunocompetent adults: an intensive 6-month study.

Clin Transl Immunology 2016 May 13;5(5):e81. Epub 2016 May 13.

Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Characterizing Epstein-Barr virus (EBV) dynamics in asymptomatic immunocompetent persons provides a baseline for defining quantitative thresholds associated with EBV disease. Studying latent membrane protein (LMP)-1 sequence variation over time could establish the rates of reactivation and superinfection, and also trace transmission. Twelve asymptomatic adult subjects were evaluated prospectively nine times over 6 months. EBV serum antibodies were measured by enzyme immunoassay. EBV DNA in oral and whole-blood samples was quantitated by real-time (TaqMan) PCR and analyzed for LMP-1 sequence variability. All 11 antibody positive subjects had EBV DNA detected in their oral compartment at least once during the 6-month study. The quantities ranged from 1.70 to 4.91 log10 copies EBV per ml of oral cell pellet. One subject was continuously viremic for 79 days. Overall, EBV DNA was detected in 63 (24%) of 260 samples from 11 antibody-positive subjects and in 0/27 samples from an antibody-negative subject. The quantities in positive samples ranged from 1.7 to 4.9 log10 copies EBV per ml. EBV LMP-1 gene sequence variations in subjects were constant over time regardless of the compartment sampled. Subjects 18-30 years old had EBV DNA detected more frequently than subjects >30 years old (38/108 positive samples versus 25/152; P<0.001). In conclusion, EBV DNA shedding is common in asymptomatic adults. The younger adults shed more frequently, which may reflect a shorter time from their primary EBV infection to sampling. The LMP-1 sequence analysis method employed here could be used to trace person-to-person transmission because patterns remained almost identical over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/cti.2016.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910122PMC
May 2016

Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer.

Br J Clin Pharmacol 2016 09 3;82(3):773-83. Epub 2016 Jun 3.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.

Aims: The aim of the present study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment.

Methods: The study enrolled 17 female patients with stages 1-3 breast cancer and receiving adjuvant doxorubicin (60 mg m(-2) ) and cyclophosphamide (600 mg m(-2) ) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP.

Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8-73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability.

Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.12989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338127PMC
September 2016

A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy.

Br J Clin Pharmacol 2016 06 3;81(6):1058-66. Epub 2016 Apr 3.

Department of Neurology, University of Minnesota, Minneapolis, MN, USA.

Aims: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys.

Methods: Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality.

Results: The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively).

Conclusions: LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.12897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876192PMC
June 2016

Pharmacokinetic-Pharmacodynamic Modeling of Intravenous and Oral Topiramate and Its Effect on the Symbol-Digit Modalities Test in Adult Healthy Volunteers.

J Clin Pharmacol 2016 06 21;56(6):714-22. Epub 2015 Dec 21.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19-55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325725PMC
June 2016

Steady-state pharmacokinetics and bioavailability of immediate-release and extended-release formulations of lamotrigine in elderly epilepsy patients: Use of stable isotope methodology.

J Clin Pharmacol 2015 Oct 18;55(10):1101-8. Epub 2015 Aug 18.

Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

A classic 2-period crossover bioavailability study was conducted to evaluate the relative and absolute bioavailability of immediate-release (IR) and extended-release (XR) lamotrigine formulations under steady-state conditions in elderly patients with epilepsy. On treatment days, each subject's morning dose (IR or XR lamotrigine) was replaced with an intravenous 50-mg dose of stable-labeled lamotrigine. Lamotrigine concentrations were measured at 13 points between 0 and 96 hours. XR and IR lamotrigine formulations were similar with respect to steady-state area under the concentration-time curve from 0 to 24 hours (AUC0-24 h ss), average concentration (Cavg, ss), and trough concentration (Cτ, ss). A 33% lower fluctuation in concentrations with XR was observed relative to IR lamotrigine. The time to peak concentration (Tmax, ss) was delayed for XR lamotrigine (3.0 vs 1.3 hours) with lower peak concentration (15% lower). The absolute bioavailability for IR and XR formulations was 73% and 92%, respectively. The formulations were bioequivalent with respect to AUC0-24 h ss, Cτ, ss, and Cavg, ss indicating that it may be possible to switch directly from IR to XR lamotrigine without changes in the total daily dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558201PMC
October 2015

Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study.

Drug Alcohol Depend 2014 Dec 24;145:185-93. Epub 2014 Oct 24.

Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, 5-130 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA.

Background: Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population.

Methods: Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac-methadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics.

Results: In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone.

Conclusion: This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2014.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254688PMC
December 2014

Pharmacokinetic-pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers.

Br J Clin Pharmacol 2015 May;79(5):820-30

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Aims: The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).

Methods: Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.

Results: Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ~100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l(-1) increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.

Conclusions: This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.12556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415718PMC
May 2015

MODEL-BASED LAMOTRIGINE CLEARANCE CHANGES DURING PREGNANCY: CLINICAL IMPLICATION.

Ann Clin Transl Neurol 2014 Feb;1(2):99-106

Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

Objective: The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines.

Methods: Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model.

Results: A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase of LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a ten-fold higher rate in 77% of the women (0.118 L/h/week) compared to 23% (0.0115 L/h/week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks.

Interpretation: The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038031PMC
February 2014

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients.

Br J Clin Pharmacol 2014 Aug;78(2):343-52

Department of Experimental and Clinical Pharmacology, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, United States; Department of Pediatrics, Division of Clinical Pharmacology and Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.

Aim: Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability.

Method: Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection. Non-linear mixed effects modelling was used to analyze the concentration-time data and evaluate demographic and transplant-related covariates.

Results: A two compartment model with first order absorption best described the data. Given the range of body sizes, clearance and volume of distribution terms were scaled using standard weight-based allometric exponents. Creatinine clearance was included on apparent oral clearance. Final estimates in a standard 70 kg individual for apparent oral clearance, central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.5 l h(-1) , 87.5 l, 4.80 l h(-1) and 42.6 l, respectively. The median terminal half-life for kidney, liver and lung transplant recipients was 9.4, 9.5 and 8.2 h, respectively. Median exposure (i.e. AUC(0,∞) in subjects taking valganciclovir 900 mg or 450 mg once daily was 57.4 and 34.3 μg ml(-1)  h, respectively.

Conclusion: Allometric scaling allowed simultaneous analysis of data from children and adults. Ganciclovir pharmacokinetics were similar among kidney, liver and lung transplant recipients. Ganciclovir exposure after valganciclovir 450 mg once daily may be suboptimal in some individuals and requires evaluation along with virologic outcomes data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.12343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137826PMC
August 2014

Pharmacometric characterization of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children.

Antimicrob Agents Chemother 2014 21;58(1):136-43. Epub 2013 Oct 21.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. The data consisted of 3,172 plasma concentrations from 96 HIV-1-infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM, and the impacts of body weight, age, race, sex, formulation, liver function, and cytochrome P450 2B6 (CYP2B6)-G516T and multidrug-resistance transporter gene (MDR1)-C3435T polymorphisms were assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid maximum-effect (Emax) maturation model demonstrated an increase in oral clearance with age to reach 90% of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90% of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance, while the MDR1-C3435T polymorphism demonstrated no effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01738-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910794PMC
September 2014