The Clinical Use of Tipranavir in HIV Infection: CHEMISTRY AND PHARMACOLOGY

24 Mar
2010

Protease inhibitors work at the last stage of the viral reproduction cycle. TPV is an inhibitor of the HIV-1 protease, thereby preventing cleavage of the polyprotein. This inhibition leads to the production of an immature, noninfec-tious virus.

The chemical structure of TPV is N-[3-[1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridine sulfonamide. Compared with the design of current PIs, the structure-based analysis design of TPV is more adaptable to alterations at the protease-binding site.

Pharmacokinetics

Because the lipophilic nature of TPV originally led to poor solubility, impaired bioavailability, and a large pill burden, a soft-gelatin capsule containing a self-emulsifying drug-delivery system (SEEDS) was developed to increase dissolution and bioavailability. The SEEDS formulation resulted in a two-fold increase in systemic concentrations, thereby cutting TPV’s pill burden in half.

TPV capsules, when coadministered with ritonavir (Abbott) should also be taken with foods that are high in fat content to increase bioavailability.

TPV is highly bound (at more than 99.9%) to plasma proteins, albumin, and alpha-1-acid glycoprotein.

TPV is metabolized primarily via the liver. It is both a substrate and an inducer of cytochrome CYP 3A4. When given with ritonavir, TPV becomes a potent inhibitor of CYP 3A4, and the concentration of TPV is thus increased. The addition of increases the maximum plasma concentration (Cmax) of TPV by 20-fold.

Elimination occurs mainly via the feces, with small amounts found in the urine. The mean elimination half-life of TPV/ ritonavir in healthy volunteers and in HIV-infected adults is approximately 4.8 and 6 hours, respectively, at steady state.

Drug Resistance

PI-associated mutations (PRAMs) and gene mutations have led to a reduced susceptibility to the current PIs. However, resistance to TPV is associated with at least three PRAMs instead of only two PRAMs, as with the older PIs.

The flexible structure of TPV is the result of a reduced number of hydrogen bonds that are required to bind to HIV-1 protease rather than to peptide PIs. This increased flexibility reduces the likelihood of the development of PI resistance. discount drugs canda

The effects of PI mutations on TPV resistance were analyzed in routine clinical samples. Although 90% of these isolates were resistant to multiple PIs, they showed less than a four-fold increase in the half-maximal inhibitory concentration (IC50). In addition, 19 isolates demonstrated more than a 2.5-fold increase in sensitivity to TPV. Confirming data indicate that no single mutation is associated with TPV resistance.

top