Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients.
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SUBMITTER: McPhail BT
PROVIDER: S-EPMC7336467 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMethadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy.MethodsWe conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference.ResultsTreatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events.ConclusionsThese results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00271219.).
| S-EPMC3073631 | biostudies-literature
Project description:BACKGROUND:Our objective was to estimate the association between methadone and neonatal abstinence syndrome compared with buprenorphine using a probabilistic bias analysis to account for unmeasured confounding by severity of addiction. METHODS:We used a cohort of live-born infants exposed in utero to methadone or buprenorphine for maternal opioid maintenance therapy at Magee-Womens Hospital in Pittsburgh, PA, from 2013 to 2015 (n = 716). We determined exposure and outcome status using pharmacy billing claims. We used log-binomial regression models to assess association of treatment with neonatal abstinence syndrome after adjusting for parity, maternal race, age, delivery year, employment, hepatitis c, smoking, marital, and insurance status. We implemented probabilistic bias analysis, informed by an internal validation study, to assess the impact of unmeasured confounding by severity of addiction. RESULTS:Infants exposed to methadone in utero were more likely to experience neonatal abstinence syndrome compared with those exposed to buprenorphine (RR, 1.3; 95% CI, 1.2, 1.5). After adjustment, infants exposed to methadone were more likely (adjusted RR, 1.3; 95% CI, 1.1, 1.5) than infants exposed to buprenorphine to have the syndrome. In the validation cohort (n = 200), severe addiction was more common in methadone- versus buprenorphine-exposed deliveries (77% vs. 32%). However, adjustment for severe addiction in the bias analysis only slightly attenuated the association (RR, 1.2; 95% CI, 1.0, 1.4), supporting conventional analysis. CONCLUSIONS:Methadone is associated with increased risk of neonatal abstinence syndrome compared with buprenorphine in infants exposed in utero. This association is subject to minimal bias due to unmeasured confounding by severity of addiction.
| S-EPMC5792296 | biostudies-literature
Project description:Neonatal abstinence syndrome (NAS)--a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine--has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS.A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study.Neonatal intensive care unit and general clinical research unit.Twenty-four neonates with NAS and five healthy adults.All participants received sublingual buprenorphine per study protocol.A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight.This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.
| S-EPMC5119858 | biostudies-literature
Project description:To characterize the population pharmacokinetics of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome and to develop a pharmacokinetic (PK) model toward an evidence-based treatment protocol.Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed by high performance liquid chromatography-tandem mass spectrometry from dried blood spots. Population PK analysis was performed to determine the volume of distribution and clearance of oral methadone. Methadone plasma concentration-time profiles were simulated from the deduced PK model to optimize the dosing regimen.There was substantial interindividual variability in methadone concentrations. Blood concentrations of methadone were best described by a 1-compartment model with first-order absorption. The population mean estimates (coefficient of variation percentage) for oral clearance and volume of distribution were 8.94 (103%) L/h/70 kg and 177 (133%) L/70 kg, respectively. Optimized dosing strategies were developed based on the simulated PK profiles. We suggest a starting dose of 0.1 mg/kg per dose every 6 hours for most patients requiring pharmacologic treatment of neonatal abstinence syndrome followed by an expedited weaning phase.The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization. Future studies should aim to validate the simulated dosing schemes with clinical data and expand our understanding of the between-patient PK variability.ClinicalTrials.gov: NCT01754324.
| S-EPMC4662899 | biostudies-literature
Project description:Increased regulatory demands for pediatric drug development research have fostered interest in the use of modeling and simulation among industry and academia. Physiologically based pharmacokinetic (PBPK) modeling offers a unique modality to incorporate multiple levels of information to estimate age-specific pharmacokinetics. This tutorial will serve to provide the reader with a basic understanding of the procedural steps to developing a pediatric PBPK model and facilitate a discussion of the advantages and limitations of this modeling technique.
| S-EPMC4260000 | biostudies-literature
Project description:AIMS:Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically-based pharmacokinetic (PBPK) model for BMS-823778 and use the model to predict PK and drug-drug interaction (DDI) in virtual populations with multiple polymorphic genes. METHODS:The PBPK model was built and verified using existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes. RESULTS:The verified PBPK model of BMS-823778 accurately recovered observed PK in different populations. In addition, the model was able to capture the exposure differences between subjects with different CYP2C19 genotypes. PK simulation indicated higher exposures of BMS-823778 in CYP2C19 poor metabolizers who were also devoid of UGT1A4 activity, compared to those with normal UGT1A4 functionality. Moderate DDI with itraconazole was predicted in subjects with wild-type CYP2C19 or UGT1A4. However, in subjects without CYP2C19 or UGT1A4 functionality, significant DDI was predicted when BMS-823778 was coadministered with itraconazole. CONCLUSIONS:A PBPK model was developed using clinical data that accurately predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was probably an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely to be dependent on the genotypes of CYP2C19 and UGT1A4.
| S-EPMC5980543 | biostudies-literature
Project description:Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin. The pediatric PBPK model was optimized following development of an adult PBPK model that adequately described literature data. We evaluated the predictability of the pediatric population PBPK model across four age groups and found that 63-93% of the observed data were captured within the 90% prediction interval of the model. We then used the pediatric PBPK model to optimize intravenous clindamycin dosing for a future prospective validation trial. The optimal dosing proposed by this model was 9 mg/kg/dose in children ?5 months of age, 12 mg/kg/dose in children >5 months-6 years of age, and 10 mg/kg/dose in children 6-18 years of age, all administered every 8 h. The simulated exposures achieved with the dosing regimen proposed were comparable with adult plasma and tissue exposures for the treatment of community-acquired methicillin-resistant Staphylococcus aureus infections. Our model demonstrated the feasibility of using opportunistic pediatric data to develop pediatric PBPK models, extending the reach of this powerful modeling tool and potentially transforming the pediatric drug development field.
| S-EPMC5597447 | biostudies-literature
Project description:To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants.Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined.For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (methadone = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition.Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine-exposed infants (36 versus 59 hours postnatal, respectively).The profile of neonatal abstinence syndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.
| S-EPMC4165073 | biostudies-literature
Project description:ObjectiveTo evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial.Study designEight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL).ResultsPrimary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01).ConclusionsInfants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment.Trial registrationClinicalTrials.gov: NCT01958476.
| S-EPMC7161698 | biostudies-literature
Project description:Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (σ1 and σ2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man.
| S-EPMC4226811 | biostudies-literature