a Department of Genitourinary Medicine and Communicable Diseases, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 1PG; b Department of HIV Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
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Abstract |
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Introduction |
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In a phase I/II study in HIV-infected patients,3 an initial dose of 4 mg/kg four times daily was well tolerated, but significant reversible elevations in hepatic transaminases were seen in two of five patients in whom the dose was increased to 6.6 mg/kg four times daily. In patients enrolled subsequently into this study, the dose of KNI-272 was increased gradually to 10 mg/kg four times daily without major abnormalities in liver function. At higher doses, there was some evidence of an antiretroviral effect.3
The objective of the current study was to assess the safety, tolerability and efficacy on surrogate markers of KNI-272 in patients with HIV infection, using a novel microsphere formulation and higher doses of the drug.
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Materials and methods |
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A dose-titration schedule was used to try to minimize the possibility of liver toxicity. Over 4 weeks the dose of the drug was increased from 6 to 24 mg/kg/day in 6 mg/kg/day increments. Each capsule of KNI-272 contained 75 mg of drug, and the number of capsules to be taken per dose was calculated to the nearest whole capsule. The drug was taken in five doses per day (the first four doses were one-sixth of the total daily dosage, and the last dose was one-third of the daily dosage). Patients who tolerated the target dose could elect to have their dose escalated further to a maximum dose of 36 mg/kg/day for the remainder of the study period. Initial dosing levels were later revised to 15 mg/kg/day, increasing to 60 mg/kg/day (or maximal tolerated dose if lower) in 15 mg/kg/day increments.
A subset of subjects underwent pharmacokinetic studies at day 1 with a single dose of 4 mg/kg, with half of the cohort fed with a standard meal and half fasted. Additional pharmacokinetic data were collected in the same cohort at day 25 when the target dose of 24 mg/kg/day had been reached.
Efficacy was measured by changes in CD4+ lymphocyte counts and plasma HIV RNA (Roche Amplicor 1.0, lower limit of detection 500 copies/mL).
For pharmacokinetic studies, blood was collected in heparinized tubes and plasma was immediately separated and stored at 20°C. Analysis of plasma for KNI-272 levels was carried out by high-performance liquid chromatography, using a validated technique with a lower limit of detection of 10 ng/mL (Huntingdon Life Sciences, Cambridge, UK).
The study was approved by the Local Research Ethics Committees at St Mary's and at the Chelsea and Westminster hospitals. Written informed consent was obtained from all subjects before participation in the trial.
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Results |
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One patient developed grade 3 elevation of alanine transaminase, and withdrew from the study. This was the only serious adverse event that was judged to be probably related to the study drug.
Pharmacokinetic results
Single-dose pharmacokinetic data are shown in Table II. For later pharmacokinetic studies, patients were dosed in the fed state. After 25 days of treatment (at which time patients were taking 24 mg/kg/day) there was no change in Cmax, AUC04 or Tmax following a dose of the drug at 4 mg/kg compared with results from patients given a single dose.
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There was no clear pattern in viral load response to treatment with KNI-272 at different final doses. Mean plasma HIV RNA decreased by 0.2 log10 from baseline to day 25 in patients on 24 mg/kg/day, but there was an increase of 0.06 log10 from baseline after 21 days of treatment at this dose. Twenty-one days after dosing at 36 and 60 mg/kg/day, changes from baseline were 0.1 and +0.23 log10, respectively.
For eight patients, full pharmacokinetic profiles and viral load data from day 25 of treatment at 24 mg/kg/day were available for an analysis that related AUC04 to change in plasma HIV RNA. This showed a weak association between exposure to KNI-272 and change in plasma HIV RNA (data not shown).
CD4+ lymphocyte count response
There was no consistent trend of change in CD4+ counts at any dose level (Table III).
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Discussion |
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Despite concerns about hepatic toxicity from other studies of KNI-272 in HIV-infected subjects, only one of the 18 patients in this study developed abnormalities in liver function tests. Since we found the drug to have a short plasma half-life, and saw no change in pharmacokinetics following administration of multiple doses nor evidence of increasing toxicity with higher doses, the dose escalation that we used to try to limit toxicity was probably unnecessary.
The formulation of KNI-272 used in this study was demonstrated to have little measurable antiretroviral activity, and had no clear effect on CD4+ lymphocyte counts. Although the drug was rapidly absorbed, the plasma half-life of the drug was very short, and there was no accumulation of the drug with repeated dosing. Since very little of the drug is excreted unchanged in the urine, it is likely that rapid metabolism of the drug accounts for the short half-life. The unfavourable pharmacokinetics of the drug might be overcome if it were given together with drugs that would inhibit metabolism of KNI-272 by cytochrome P450. For example, co-administration of KNI-272 with ritonavir, indinavir, nelfinavir or delavirdine to rats led to increases in AUC for KNI-272 of up to 22-fold.6 It remains to be seen, however, whether a similar effect is seen in human subjects, and whether the increased drug exposure that would result would be associated with any additional toxicity.
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Notes |
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References |
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2 . Kageyama, S., Anderson, B. D., Hoesterey, B. L., Hayashi, H., Kiso, Y., Flora, K. P. et al. (1994). Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins. Antimicrobial Agents and Chemotherapy 38, 110711.[Abstract]
3 . Humphrey, R. W., Wyvill, K. M., Nguyen, B. Y., Shay, L. E., Kohler, D. R., Steinberg, S. M. et al. (1999). A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection. Antiviral Research 41, 2133.[ISI][Medline]
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Hammer, S. M., Squires, K. E., Hughes, M. D., Grimes, J. M., Demeter, L. M., Currier, J. S. et al. (1997). A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. New England Journal of Medicine 337, 72533.
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Palella, F. J., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. New England Journal of Medicine 338, 85360.
6 . Sato, H., Shintani, M. S., Mimoto, T. M., Terashima, K. T., Hayashi, H. H. & Mitsuya, H. M. (1998). In vitro antiviral activity and pharmacokinetic (PK) profiles of KNI-272 when combined with other protease inhibitors (PIs). XIIth World AIDS Conference, Geneva, 1998. Abstract 12339.
Received 10 January 2000; returned 3 May 2000; revised 25 September 2000; accepted 17 October 2000