591
Therapeutic Drug Monitoring of Boosted Tipranavir with and without Combination to Lopinavir or Fosamprenavir
Gilles Peytavin*1, A Marcelin2, A Rouault1, M Bonmarchand2, H Aït-Mohand2, B Cassard1, L Schneider2, D Costagliola3, V Calvez2, and C Katlama2
1Hosp Bichat, Paris, France; 2Hosp Pitié-Salpétrière, Paris, France; and 3INSERM EMI 0214, Paris, France
Background: Double protease inhibitor (PI)
boosting represents a new strategy particularly suitable in the salvage
setting. Previous data demonstrated that amprenavir
(APV) and lopinavir (LPV) trough plasma
concentrations (Cmin) were decreased by
approximately 56% and 45% in combination with tipranavir (TPV; a potent CYP3A4 inducer) compared with
those obtained with standard doses of APV/ritonavir
(RTV) and LPV/RTV alone, respectively. Our objective was to describe the TPV, APV, and LPV
drug-drug interactions at steady-state and to propose fos-APV or LPV
dose adjustments to increase the respective Cmin
in association with TPV.
Methods:
TPV, APV, and LPV Cmin (12 hours after the last drug intake) were performed using high performance liquid chromatography (HPLC) methods in HIV-1-infected patients treated with TPV/RTV (500/200
mg) with and without fos-APV (700 mg) or LPV (400 mg)
twice daily combination. TDM consisted in an increase of fos-APV/RTV
dose to 1400/200 mg twice daily or LPV/RTV dose to 533/233 mg twice daily..
Results: Among
the 190 (162 males, 44 years old), highly experienced
patients treated with
TPV, 20 received LPV and 32 fos-APV. In the whole
population, TPV Cmin were
28,350 ng/mL (14,036 to 48,046; 408). Of them, 21%
were below 12,000 ng/mL (20 µM), considered as the
effective antiviral cut-off and only 3% below 100 ng/mL
(LOQ) were considered as non adherent. Before TDM, APV, and LPV Cmin were 570 ng/mL
(267 to 1,014; 22) and 4257 ng/mL (1894 to 5938; 40),
and after TDM, APV, and LPV Cmin were 1193
ng/mL (649 to 1,884; 39) and 6151 ng/mL
(2652 to 9623; 19), respectively (p =
0.008; p <0.0001). Despite a wide
inter-patient variability, APV and LPV median Cmin
were increased by 48% and 58%, respectively. RTV and TPV Cmin
were statistically related (p
<0.0001).
Conclusions: Previous results on TPV Cmin
variability and enzymatic induction were confirmed in the present study. TDM
should be helpful to adjust fos-APV and LPV doses
allowing the combination with TPV in a double-boosted combination.
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