TIBO Report: Good Pharmacokinetics, No Dramatic Benefit

TIBO derivatives are a class of very selective inhibitors of HIV; because of their selectivity, they are expected to have low toxicity as drugs. TIBO derivatives are reverse- transcriptase inhibitors, but (unlike AZT, ddI, and ddC) not nucleoside analogs. Low-profile human studies of this class of drugs have been occurring in Europe for over a year. AIDS TREATMENT NEWS covered TIBO derivatives in issue #97 (February 16, 1990), but we did not include them in our survey of new-generation antivirals (issue #129, April 12, 1991) because little information was available, and the reports we did hear about human testing were mostly unfavorable.

On July 20 The Lancet published a report of a 50-week, 22- patient study in England of R 82913, one of the drugs in this class1; this study was also described at the recent International Conference on AIDS in Florence2. The drug was well tolerated and showed good pharmacokinetics, with stable blood values when given intravenously, but evidence for efficacy was small. (The recent publication was widely reported in the press, but sometimes mistakenly attributed to the wrong journal, Nature instead of The Lancet.)

The study reported was not primarily designed to look for efficacy. Instead, for each volunteer daily doses were escalated from 10 to 300 mg; the latter gave trough levels (the lowest blood concentrations during the day) which were enough to inhibit HIV in laboratory tests. All 22 volunteers had advanced HIV infection; all T-helper counts were below 300, all had opportunistic infections before the study began, and all but one were p24 antigen positive.

Average T-helper counts rose slightly when the maximum drug level was attained. Also, p24 antigen fell 41 percent during the first month of treatment; before treatment, it had been rising. None of the volunteers showed great clinical improvement, however, and most continued to lose weight. Seven patients died during the study: two of them had KS, four began the trial with T- cell counts below 20, and the other died of PML (progressive multifocal leukoencephalopathy). Nine others who left the trial are still alive; the other six were still receiving treatment in January 1991.

The data suggested that larger doses of R 82913 may be needed; it is often difficult to predict required levels of antivirals based on laboratory tests. However, the drug is difficult to make, and there was little available when this trial was run -- perhaps not enough to test higher doses.

A graph published with the paper showed that there was about a 10-fold difference between peak and trough blood concentrations of the drug -- despite daily dosing and an elimination half-life of three days. It is possible that more frequent dosing would help.

The lack of toxicity of R 82913 suggests that this drug might prove useful when enough of it becomes available to test higher doses.

References

Pialoux G, Youle M, Dupont B and others. Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex. The Lancet. July 20,1991; volume 338, pages 140-143.

Pialoux G, Youle M, Dupont B, Gazzard B, Cauwenbergh G, and Janssen PAJ. Early clinical evaluation of R 82913 TIBO compound in patients with severe HIV infection. Abstract #Th.B. 86, Seventh International Conference on AIDS, Florence, June 16-21, 1991.