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Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics.

ABSTRACT: Central nervous system drug discovery and development is hindered by the impermeable nature of the blood-brain barrier. Pharmacokinetic modeling can provide a novel approach to estimate CNS drug exposure; however, existing models do not predict temporal drug concentrations in distinct brain regions. A rat CNS physiologically based pharmacokinetic (PBPK) model was developed, incorporating brain compartments for the frontal cortex (FC), hippocampus (HC), "rest-of-brain" (ROB), and cerebrospinal fluid (CSF). Model predictions of FC and HC Cmax, tmax and AUC were within 2-fold of that reported for carbamazepine and phenytoin. The inclusion of a 30% coefficient of variation on regional brain tissue volumes, to assess the uncertainty of regional brain compartments volumes on predicted concentrations, resulted in a minimal level of sensitivity of model predictions. This model was subsequently extended to predict human brain morphine concentrations, and predicted a ROB Cmax of 21.7 ± 6.41 ng/mL when compared to "better" (10.1 ng/mL) or "worse" (29.8 ng/mL) brain tissue regions with a FC Cmax of 62.12 ± 17.32 ng/mL and a HC Cmax of 182.2 ± 51.2 ng/mL. These results indicate that this simplified regional brain PBPK model is useful for forward prediction approaches in humans for estimating regional brain drug concentrations.

SUBMITTER: Zakaria Z

PROVIDER: S-EPMC5874827 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics.

Zakaria Zaril Z Badhan Raj R

Pharmaceutics 20180117 1

Central nervous system drug discovery and development is hindered by the impermeable nature of the blood-brain barrier. Pharmacokinetic modeling can provide a novel approach to estimate CNS drug exposure; however, existing models do not predict temporal drug concentrations in distinct brain regions. A rat CNS physiologically based pharmacokinetic (PBPK) model was developed, incorporating brain compartments for the frontal cortex (FC), hippocampus (HC), "rest-of-brain" (ROB), and cerebrospinal fl ...[more]

PMID: 29342085

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Project description:BackgroundBecause of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear.ObjectivesThe goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group.MethodsFor parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim®. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations-with regard to age, sex, anthropometric measures and dosage-were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ss) values and elimination half-life (t ½) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly.ResultsFor most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V ss and t ½ values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes.ConclusionThe results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to optimize drug therapy in elderly individuals. These results indicate that pharmacotherapy and safety-related control of geriatric drug therapy regimens may be greatly facilitated by the information gained from PBPK predictions.

Project description:Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

Dataset Information

Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics.

Publications

Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics.

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