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Article ; Online: Population Pharmacokinetic Modeling and Exposure-Response Analysis for Aripiprazole Once Monthly in Subjects With Schizophrenia.

Wang, Xiaofeng / Raoufinia, Arash / Bihorel, Sébastien / Passarell, Julie / Mallikaarjun, Suresh / Phillips, Luann

Clinical pharmacology in drug development

2022 Volume 11, Issue 2, Page(s) 150–164

Abstract: An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative ...

Abstract	An intramuscular formulation of aripiprazole monohydrate dosed once monthly (AOM) was developed to address nonadherence with the approved oral tablets. A 3-compartment linear population pharmacokinetic model for oral and AOM doses was developed; relative bioavailability was estimated for AOM relative to oral dosing and body mass index and sex were significant predictors of AOM absorption rate constant (longer absorption half-life for women and absorption half-life increases with increasing body mass index). Aripiprazole apparent oral clearance for subjects with cytochrome P450 (CYP) 2D6 poor metabolizer status and in the presence of strong CYP2D6 inhibitors was approximately half that of subjects with CYP2D6 extensive metabolizer status and 24% lower in the presence of strong CYP3A4 inhibitors. Simulations of the population pharmacokinetics were conducted to evaluate the effect of different dose initiation strategies for AOM, the effects of CYP2D6 metabolizer status, coadministration of CYP2D6 and CYP3A4 inhibitors, and missed doses. An exposure-response model with an exponential hazard function of the model-predicted minimum concentration (C
MeSH term(s)	Antipsychotic Agents ; Aripiprazole ; Female ; Humans ; Piperazines/pharmacokinetics ; Quinolones/pharmacokinetics ; Schizophrenia/drug therapy
Chemical Substances	Antipsychotic Agents ; Piperazines ; Quinolones ; Aripiprazole (82VFR53I78)
Language	English
Publishing date	2022-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1022
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Article ; Online: Exposure-response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder.

Darwish, Mona / Dirks, Bryan / Passarell, Julie / Jaworowicz, David / Bihorel, Sebastien / Howell, Becky / Owen, Joel / DeKarske, Daryl / Stankovic, Srdjan

Clinical pharmacology in drug development

2023 Volume 12, Issue 5, Page(s) 463–474

Abstract: In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score ( ... ...

Abstract	In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure-response (E-R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population-pharmacokinetic empirical Bayesian estimates. E-R models were developed to describe exposure-efficacy (HAMD-17, SDS, and Clinical Global Impression-Improvement [CGI-I] scale) and exposure-safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD-17 scores), a sigmoid maximum-effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD-17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (C
MeSH term(s)	Humans ; Depressive Disorder, Major/drug therapy ; Bayes Theorem ; Antidepressive Agents/adverse effects ; Piperidines/adverse effects
Chemical Substances	pimavanserin (JZ963P0DIK) ; Antidepressive Agents ; Piperidines
Language	English
Publishing date	2023-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1232
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Article ; Online: Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

Wiegman, Albert / Greber-Platzer, Susanne / Ali, Shazia / Reijman, M Doortje / Brinton, Eliot A / Charng, Min-Ji / Srinivasan, Shubha / Baker-Smith, Carissa / Baum, Seth / Brothers, Julie A / Hartz, Jacob / Moriarty, Patrick M / Mendell, Jeanne / Bihorel, Sébastien / Banerjee, Poulabi / George, Richard T / Hirshberg, Boaz / Pordy, Robert

Circulation

2023 Volume 149, Issue 5, Page(s) 343–353

Abstract: Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely ... ...

Abstract	Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. Methods: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. Results: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. Conclusions: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.
MeSH term(s)	Adolescent ; Humans ; Child ; Cholesterol, LDL/genetics ; Homozygous Familial Hypercholesterolemia ; Hyperlipoproteinemia Type II/diagnosis ; Hyperlipoproteinemia Type II/drug therapy ; Hyperlipoproteinemia Type II/genetics ; Anticholesteremic Agents/adverse effects ; Homozygote ; Antibodies, Monoclonal
Chemical Substances	Cholesterol, LDL ; evinacumab (T8B2ORP1DW) ; Anticholesteremic Agents ; Antibodies, Monoclonal
Language	English
Publishing date	2023-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.123.065529
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Article ; Online: Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

Jaworowicz, David / Bihorel, Sébastien / Zajic, Stefan / Stoch, S Aubrey / Humphrey, Rebecca / McCrea, Jacqueline B / Stone, Julie A

Journal of clinical pharmacology

2020 Volume 60, Issue 8, Page(s) 1107–1123

Abstract: This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase ...

Abstract	This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.
Language	English
Publishing date	2020-04-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1606
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Article ; Online: Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 12, Page(s) 1859–1871

Abstract: Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for ...

Abstract	Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.
MeSH term(s)	Adult ; Humans ; Antiviral Agents ; Body Mass Index ; COVID-19 ; Hydroxylamines ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Hydroxylamines ; molnupiravir (YA84KI1VEW)
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Clinical Trial ; Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13031
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Article ; Online: Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Bihorel, Sébastien / Singhal, Shalabh / Shevell, Diane / Sun, Huadong / Xie, Jenny / Basdeo, Shenita / Liu, Ang / Dutta, Santanu / Ludwig, Elizabeth / Huang, Hannah / Lin, Kuan-Ju / Fura, Aberra / Throup, John / Girgis, Ihab G

Clinical pharmacology in drug development

2020 Volume 10, Issue 1, Page(s) 8–21

Abstract: Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to ... ...

Abstract	Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.
MeSH term(s)	Adult ; Computer Simulation ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Healthy Volunteers ; Heart Rate/drug effects ; Humans ; Lymphocyte Count ; Male ; Middle Aged ; Models, Biological ; Sphingosine-1-Phosphate Receptors ; Tetrahydronaphthalenes/administration & dosage ; Tetrahydronaphthalenes/pharmacokinetics ; Young Adult
Chemical Substances	BMS-986166 ; Sphingosine-1-Phosphate Receptors ; Tetrahydronaphthalenes
Language	English
Publishing date	2020-10-08
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.878
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Article ; Online: Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.

Bihorel, Sébastien / Fiedler-Kelly, Jill / Ludwig, Elizabeth / Sloan-Lancaster, Joanne / Raddad, Eyas

The AAPS journal

2014 Volume 16, Issue 5, Page(s) 1009–1017

Abstract: Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized ... ...

Abstract	Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02-2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432-0.721) and absorption half-life (94.3-157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing.
MeSH term(s)	Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/blood ; Anti-Inflammatory Agents/pharmacokinetics ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/blood ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/immunology ; Biological Availability ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/immunology ; Drug Administration Schedule ; Drug Dosage Calculations ; Half-Life ; Humans ; Hypoglycemic Agents/administration & dosage ; Hypoglycemic Agents/blood ; Hypoglycemic Agents/pharmacokinetics ; Injections, Intravenous ; Injections, Subcutaneous ; Linear Models ; Metabolic Clearance Rate ; Models, Biological ; Randomized Controlled Trials as Topic ; Treatment Outcome
Chemical Substances	Anti-Inflammatory Agents ; Antibodies, Monoclonal, Humanized ; Hypoglycemic Agents ; LY2189102
Language	English
Publishing date	2014-06-11
Publishing country	United States
Document type	Comparative Study ; Journal Article
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-014-9623-6
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Article: Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar.

Bihorel, Sébastien / Camenisch, Gian / Lemaire, Michel / Scherrmann, Jean-Michel

Pharmaceutical research

2007 Volume 24, Issue 9, Page(s) 1720–1728

Abstract: Purpose: The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and ... ...

Abstract	Purpose: The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and Breast cancer resistance protein (rodent Bcrp1 or Abcg2) were suggested to restrict the delivery of imatinib to the brain. This study evaluates the effect of administering selective inhibitors of these transporters together with imatinib on the systemic and cerebral disposition of imatinib in mice. Materials and methods: Wild-type, Mdr1a/1b(-/-) and Bcrp1(-/-) mice were given imatinib intravenously, either alone, or with valspodar, zosuquidar (P-gp inhibitors), or elacridar (a P-gp and Bcrp1 inhibitor). The blood and brain concentrations of [(14)C]imatinib and its radioactive metabolites were determined. Results: The blockade of P-gp by valspodar or zosuquidar (>3 mg/kg) enhanced the brain uptake of imatinib ( approximately 4-fold) in wild-type mice, but not that of its metabolites. Blockade of both P-gp and Bcrp1 by elacridar (>3 mg/kg) produced significantly greater brain penetration of imatinib (9.3-fold) and its metabolites (2.8-fold). In contrast, only the lack of P-gp enhanced imatinib brain penetration (6.4-fold) in knockout mice. These results of brain uptake correlated reasonably well with those obtained previously by our group using in situ brain perfusion. Conclusions: Imatinib and its metabolites penetrate into the brain poorly and their penetration is limited by P-gp and (probably) Bcrp1. Administering imatinib together with P-gp (and Bcrp1) transporter inhibitors such as elacridar may improve the delivery of imatinib to the brain, making it potentially more effective against malignant gliomas.
MeSH term(s)	ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters/physiology ; ATP-Binding Cassette, Sub-Family B, Member 1/physiology ; Acridines/pharmacology ; Animals ; Antineoplastic Agents/pharmacokinetics ; Benzamides ; Blood-Brain Barrier ; Brain/metabolism ; Carbon Radioisotopes ; Cyclosporins/pharmacology ; Dibenzocycloheptenes/pharmacology ; Imatinib Mesylate ; Male ; Mice ; Piperazines/pharmacokinetics ; Protein Kinase Inhibitors/pharmacokinetics ; Pyrimidines/pharmacokinetics ; Quinolines/pharmacology ; Tetrahydroisoquinolines/pharmacology
Chemical Substances	ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette, Sub-Family B, Member 1 ; Abcg2 protein, mouse ; Acridines ; Antineoplastic Agents ; Benzamides ; Carbon Radioisotopes ; Cyclosporins ; Dibenzocycloheptenes ; Piperazines ; Protein Kinase Inhibitors ; Pyrimidines ; Quinolines ; Tetrahydroisoquinolines ; zosuquidar trihydrochloride (813AGY3126) ; Imatinib Mesylate (8A1O1M485B) ; Elacridar (N488540F94) ; valspodar (Q7ZP55KF3X)
Language	English
Publishing date	2007-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-007-9278-4
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Article: Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier.

Bihorel, Sébastien / Camenisch, Gian / Lemaire, Michel / Scherrmann, Jean-Michel

Journal of neurochemistry

2007 Volume 102, Issue 6, Page(s) 1749–1757

Abstract: Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance ... ...

Abstract	Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Acridines/pharmacology ; Animals ; Antineoplastic Agents/metabolism ; Benzamides ; Biological Transport, Active/drug effects ; Biological Transport, Active/physiology ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/blood supply ; Brain/drug effects ; Brain/metabolism ; Cyclosporins/pharmacology ; Dibenzocycloheptenes/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Imatinib Mesylate ; Immunosuppressive Agents/pharmacology ; Male ; Mice ; Mice, Knockout ; Piperazines/metabolism ; Piperazines/pharmacokinetics ; Pyrimidines/metabolism ; Pyrimidines/pharmacokinetics ; Quinolines/pharmacology ; Tetrahydroisoquinolines/pharmacology
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Abcg2 protein, mouse ; Acridines ; Antineoplastic Agents ; Benzamides ; CGP 74588 ; Cyclosporins ; Dibenzocycloheptenes ; Enzyme Inhibitors ; Immunosuppressive Agents ; Piperazines ; Pyrimidines ; Quinolines ; Tetrahydroisoquinolines ; zosuquidar trihydrochloride (813AGY3126) ; Imatinib Mesylate (8A1O1M485B) ; multidrug resistance protein 3 (9EI49ZU76O) ; Abcb1b protein, mouse (EC 7.6.2.2) ; Elacridar (N488540F94) ; valspodar (Q7ZP55KF3X)
Language	English
Publishing date	2007-08-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/j.1471-4159.2007.04808.x
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Article ; Online: Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats.

Gao, Wei / Bihorel, Sébastien / DuBois, Debra C / Almon, Richard R / Jusko, William J

Journal of pharmacokinetics and pharmacodynamics

2010 Volume 38, Issue 1, Page(s) 143–162

Abstract: The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated ... ...

Abstract	The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated hemoglobin (HbA1c) changes over time. The study included 30 WKY and 30 GK rats. Plasma glucose and insulin, blood glucose and HbA1c concentrations and hematological measurements were taken at ages 4, 8, 12, 16 and 20 weeks. A mathematical model described the development of insulin resistance (IR) and β-cell function with age/growth and diabetes progression. The model utilized transit compartments and an indirect response model to quantitate biomarker changes over time. Glucose, insulin and HbA1c concentrations in WKY rats increased to a steady-state at 8 weeks due to developmental changes. Glucose concentrations at 4 weeks in GK rats were almost twice those of controls, and increased to a steady-state after 8 weeks. Insulin concentrations at 4 weeks in GK rats were similar to controls, and then hyperinsulinemia occurred until 12-16 weeks of age indicating IR. Subsequently, insulin concentrations in GK rats declined to slightly below WKY controls due to β-cell failure. HbA1c showed a delayed increase relative to glucose. Modeling of HbA1c was complicated by age-related changes in hematology in rats. The diabetes model quantitatively described the glucose/insulin inter-regulation and HbA1c production and reflected the underlying pathogenic factors of T2D--IR and β-cell dysfunction. The model could be extended to incorporate other biomarkers and effects of various anti-diabetic drugs.
MeSH term(s)	Animals ; Blood Glucose ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Disease Progression ; Feedback, Physiological ; Glycated Hemoglobin A/analysis ; Hematologic Tests ; Insulin/blood ; Male ; Models, Biological ; Rats ; Rats, Inbred Strains ; Rats, Inbred WKY
Chemical Substances	Blood Glucose ; Glycated Hemoglobin A ; Insulin ; hemoglobin A1c protein, human
Language	English
Publishing date	2010-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-010-9182-0
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