Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures.
OBJECTIVE
To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg).


METHODS
Two-parallel groups, addition of LPV in patients receiving ATV (n=6), and addition of ATV in patients receiving LPV (n=7), with before/after comparisons.


METHODS
Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI). Total plasma concentrations (Ctot) were analysed by HPLC-UV and unbound plasma concentrations (Cu) and cellular concentrations (Ccell) were analysed by LC-MS/MS. Plasma and cellular PK parameters were also calculated. Unbound and cellular fractions were expressed as Cu/Ctot and Ccell/Ctot ratio. Data were analysed by paired Student t-test on log values; correlations between Ccell, Cu and Ctot were explored by log-log linear regression.


RESULTS
Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV was associated with a decrease in LPV concentrations (by 16% for area under the time-concentration curve, maximum concentration and trough concentration, NS; and by 35% for Cmin, P=0.04). The RTV PK parameters remained unmodified. The Ccell/Ctot and Cu/Ctot ratio was unaffected by the addition of the second PI and remained stable throughout dosing interval. Good correlations were observed between Ccell, Cu and Ctot for each drug. No relevant toxicity was observed.


CONCLUSIONS
Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV caused a limited decrease in LPV concentrations. The clinical significance of this decrease is unknown and warrants further investigation to determine the need for tailoring LPV dosage in selected cases.
Colombo
Sara
S
Division of Clinical Pharmacology and Toxicology, University Hospital of Lausanne, Switzerland.
Buclin
Thierry
T
Franc
Claudia
C
Guignard
Nicole
N
Khonkarly
Mona
M
Tarr
Philip E
PE
Rochat
Bertrand
B
Biollaz
Jérôme
J
Telenti
Amalio
A
Decosterd
Laurent A
LA
Cavassini
Matthias
M
D000328:Adult; D000069446:Atazanavir Sulfate; D001798:Blood Proteins / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D001798:Blood Proteins; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir