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Abacavir Plasma Pharmacokinetics in the Absence and the Presence of Atazanavir/Ritonavir or Lopinavir/Ritonavir) and Vice Versa in HIV+ Patients
Laura Waters*1, G Moyle1, A D’Avolio2, M Sciandra2, L Else3, A Pozniak1, M Nelson1, B Gazzard1, D Back3, and M Boffito1
1Chelsea and Westminster Hosp, London, UK; 2Univ of Turin, Italy; and 3Univ of Liverpool, UK
Background:
Abacavir (ABC)
is metabolized by alcohol dehydrogenase and glucuronyl transferase. Nucleoside reverse transcriptase
inhibitors (NRTI) and protease inhibitors (PI) do not share known metabolic
pathways, yet drug interactions between tenofovir (TDF) and atazanavir/ritonavir
(ATV/r) or lopinavir/ritonavir (LPV/r) have been
observed and transport proteins implicated. We aimed to investigate ABC pharmacokinetics
in the absence and presence of ATV/r or LPV/r and vice versa in HIV+
patients.
Methods: HIV+ subjects on ART: A) ABC 600 mg once daily plus 2 NRTI (not TDF)
underwent 24-hour pharmacokinetic assessment for steady-state plasma ABC
concentrations on day 1. On day 2, they added ATV/r (300/100 mg once daily) or
LPV/r (400/100 mg twice daily) and on day 15 repeated 24-hour pharmacokinetic
assessment; B) ATV/r or LPV/r and 2 NRTI (not TDF or ABC) underwent 24- or 12-hour
pharmacokinetic assessment for steady-state plasma ATV/r or LPV/r
concentrations on day 1. On day 2, they added ABC 600 mg once daily and on day
15 repeated 24-hour pharmacokinetic assessment. Pharmacokinetic parameters were
calculated using non-compartmental modelling (WinNonlin®).
Within-subject changes in pharmacokinetic parameters were evaluated by
calculating geometric mean (GM) ratios and 95% confidence intervals (CI) determined
using logs of the individual GM and expressed as linear values.
Results: Of the 24 patients
who completed the study, 3 were females and median age was 4 3years. Baseline
median (range) CD4 was 525 (144 to 1181), all had a viral load <200. Median
(range) ABC AUC (ng.h/mL) and Cmax
(ng/mL, n =
12) were 18,217 (10,362 to 21,992) and 4258 (2322 to 7949). Following addition
of ATV/r (n = 6) they were 15267 (11,783
to 18,423) and 3390 (2359 to 5184). Following addition of LPV/r (n = 6) they were 10,934 (8107 to 12,313)
and 2875 (2396 to 4647). ATV (n = 6)
AUC and Cmax without and with ABC were 21,861
(10,709 to 10,9976) and 27,698 (17,404 to 70,582), and
2539 (1079 to 8763) and 2767 (1621 to 6298). LPV (n = 6) AUC and Cmax without
and with ABC were 71,700 (42,749 to 92,174) and 57,336 (54,645 to 11,5481), and 8763 (4984 to 12,439) and 8075 (6645 to 13,897).
AUC and Cmax GM ratios (95%CI) of ABC
without and with ATV/r were 0.83 (0.78 to 0.88) and 0.80 (0.66 to 0.97). AUC
and Cmax GM ratios (95%CI) of ABC without
and with LPV/r were 0.68 (0.59 to 0.79) and 0.66 (0.54 to 0.82). GM ratios for ATV and LPV pharmacokinetic
parameters did not differ from unity.
Conclusions:
No changes in ATV, LPV, and r exposures
were observed following addition of ABC. However, mild (17%) and moderate (32%)
decreases in ABC plasma exposure were observed following addition of ATV/r or
LPV/r, respectively. The mechanism of
interaction, the impact on intracellular triphosphates
and the clinical implications should be investigated further.
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