Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients.
OBJECTIVE
To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients.


METHODS
Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined.


RESULTS
In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02).


CONCLUSIONS
The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.
Ford
Jennifer
J
Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, and PK Research Ltd., St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
Boffito
Marta
M
Maitland
Desmond
D
Hill
Andrew
A
Back
David
D
Khoo
Saye
S
Nelson
Mark
M
Moyle
Graeme
G
Gazzard
Brian
B
Pozniak
Anton
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000097:blood; D000328:Adult; D000069446:Atazanavir Sulfate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006678:HIV / Q000302:isolation & purification*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood; D009363:Neoplasm Proteins / Q000097:blood; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000069446:Atazanavir Sulfate; D017320:HIV Protease Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011725:Pyridines; D019438:Ritonavir; D019258:Saquinavir; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1