Central nervous system pharmacokinetics of the Mdr1 P-glycoprotein substrate CP-615,003: intersite differences and implications for human receptor occupancy projections from cerebrospinal fluid exposures.
The central nervous system (CNS) distribution and transport mechanisms of the investigational drug candidate CP-615,003 (N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide) and its active metabolite CP-900,725 have been characterized. Brain distribution of CP-615,003 and CP-900,725 was low in rats and mice (brain-to-serum ratio < 0.2). Cerebrospinal fluid (CSF)-to-serum ratios of CP-615,003 were 6- to 8-fold lower than the plasma unbound fraction in rats and dogs. In vitro, CP-615,003 displayed quinidine-like efflux in MDR1-expressing Madin-Darby canine kidney II cells. The brain-to-serum ratio of CP-615,003 in mdr1a/1b (-/-) mice was approximately 7 times that in their wild-type counterparts, confirming that impaired CNS distribution was explained by P-gp efflux transport. In contrast, P-gp efflux did not explain the impaired CNS penetration of CP-900,725. Intracerebral microdialysis was used to characterize rat brain extracellular fluid (ECF) distribution. Interestingly, the ECF-to-serum ratio of the P-gp substrate CP-615,003 was 7-fold below the CSF-to-serum ratio, whereas this disequilibrium was not observed for CP-900,725. In a clinical study, steady-state CSF exposures were measured after administration of 100 mg of CP-615,003 b.i.d. The human CSF-to-plasma ratios of CP-615,003 and CP-900,725 were both approximately 10-fold below their ex vivo plasma unbound fractions, confirming impaired human CNS penetration. Preliminary estimates of CNS receptor occupancy from human CSF concentrations were sensitive to assumptions regarding the magnitude of the CSF-ECF gradient for CP-615,003 in humans. In summary, this case provides an example of intersite differences in CNS pharmacokinetics of a P-gp substrate and potential implications for projection of human CNS receptor occupancy of transporter substrates from CSF pharmacokinetic data when direct imaging-based approaches are not feasible.
Venkatakrishnan
Karthik
K
Department of Clinical Pharmacology, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. karthik.venkatakrishnan@pfizer.com
Tseng
Elaine
E
Nelson
Frederick R
FR
Rollema
Hans
H
French
Jonathan L
JL
Kaplan
Irina V
IV
Horner
Weldon E
WE
Gibbs
Megan A
MA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004285:Dogs; D045604:Extracellular Fluid / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D006801:Humans; D007211:Indoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D058785:GABA-A Receptor Agonists; D007211:Indoles; D011963:Receptors, GABA-A; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C095122:multidrug resistance protein 3; C512159:N-(3-fluoro-4-(2-(propylamino)ethoxy)phenyl)-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide