Population pharmacokinetic/ pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV‐positive patients

Abstract

BACKGROUNDMaraviroc, a noncompetitive antagonist of the CCR5 coreceptor, was recently approved in the USA as a treatment of HIV infection. For antiretroviral agents that target the virus, antiviral effect can be related to some extent to plasma drug concentrations. For CCR5 antagonists that target the host cells, receptor occupancy in vivo might be a better predictor of efficacy. AIMSTo develop a population pharmacokinetic (PK)-pharmacodynamic (PD) model that describes CCR5 receptor occupancy by maraviroc after oral administration at different doses in healthy volunteers and HIV-positive patients and to assess the relevance of receptor occupancy in predicting the decrease in viral load (HIV-1 RNA copies ml METHODSReceptor occupancy data from 88 individuals enrolled in two multiple dose trials were included in the population PK-receptor binding model. Out of the 88 individuals, 25 were HIV-1-infected patients and had viral load measurements, whereas the remaining 63 were healthy volunteers. Doses ranged from 3 mg b.i.d. to 600 mg q.d. A previously published PK-PD disease model describing the effect of maraviroc on the viral load was updated by replacing its PD module by the receptor occupancy model. Simulated viral load-time profiles with the updated model were compared with the profiles observed in patients. RESULTSThe majority of measured plasma concentrations were associated with receptor occupancy Ն50% even at the lowest dose of 3 mg b.i.d. A simple direct Emax model appeared to describe satisfactorily the PK-receptor occupancy relationship. The estimated KD was around 0.0894 ng ml . Accordingly, simulations led to marked overprediction of the decrease in viral load-time profiles. CONCLUSIONSMaraviroc receptor occupancy close to the maximum is required to induce a significant decrease in viral load, indicating that in vivo CCR5 receptor occupancy by maraviroc is not a direct measure of drug inhibitory activity. Considering the imprecision of the measurement in the upper flat part of the maraviroc concentration vs. percent CCR5 occupancy curve, it can reasonably be concluded that routine monitoring of receptor occupancy as a biomarker for maraviroc efficacy will not be helpful. Based on this analysis, it was decided not to use receptor occupancy as a biomarker of viral load inhibition during the development of CCR5 antagonist compounds.

Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues

“…This observation is consistent with clinical studies showing that almost complete CCR5 occupancy is required to significantly reduce plasma viremia (29) and suggests that only a few unoccupied receptors may be sufficient to initiate and sustain a spreading infection. However, as with human CCR5, rhesus CCR5 was not fully internalized by MIP-1␤ in PBMCs or rectal leukocytes in the in vitro assay, thus limiting our analysis to the proportion of CCR5 that was downregulated by MIP-1␤ ex vivo (31).…”

“…The binding of MVC to CCR5 was determined ex vivo using a MIP-1␤ internalization assay previously described (27)(28)(29). In this assay, free CCR5 receptors in the cell surface are internalized upon stimulation with MIP-1␤, which is a natural ligand of CCR5 (30).…”

Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures

“…Maraviroc dose selection for the phase 2b/3 trials was based on in vitro virology (in vitro protein-adjusted IC 90 = 2.1 ng/ml) (Dorr et al, 2005), PK-viral dynamics modeling utilizing a broad range of doses in monotherapy (in vivo IC 50 of 8 ng/ml) (Rosario et al, 2008), and an extensive healthy volunteer drug interaction program (Abel et al, 2009). In a maraviroc monotherapy study, greater than 80% viral inhibition (range: 88-96%) was demonstrated with PK-viral dynamics modeling at exposures observed with 300 mg BID (C avg [AUC divided by the dosing interval] range: 141-338 ng/ml) (Fatkenheuer et al, 2005;Rosario et al, 2006).…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…RO assays are typically performed on fresh blood specimens in order to minimize the probability of drug dissociation from target receptors during sample processing. Current efforts to stabilize blood with traditional paraformaldehyde‐based fixatives often lead to unacceptable levels of signal loss or increased background staining levels 59. Ultimately, the ability to more effectively stabilize blood specimens immediately following collection would likely reduce variability and enable for a more quantitative assessment of RO.…”