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Clinical Aspects of Treatment with Tipranavir. Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK. Profile and Pharmacokinetics. Tipranavir Profile. The first in a new generation of PIs Non-peptidic structure: less Hydrogen bonds gives flexible binding
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Clinical Aspects of Treatment with Tipranavir Dr Kevin CurryBoehringer Ingelheim, Bracknell, UK
TipranavirProfile • The first in a new generation of PIs • Non-peptidic structure: less Hydrogen bonds gives flexible binding • Retains in vitro activity against >90% of HIV-1 strains resistant to first generation PIs • Potent in vitro activity against wild-type HIV-1 and HIV-2 strains
TipranavirProfile • Wild Type EC90 0.5-1.0 M • Target Cmin for multiple PI resistant HIV-1 • 20 µM • 10x Protein adjusted EC90 for multiple PI resistant HIV-1
Tipranavir Pharmacokinetics • TPV exhibits linear pharmacokinetics • TPV exposure is markedly enhanced by rtv • TPV is a potent inducer of CYP3A • This is overwhelmed by rtv
ARV Naïve Patients Mean (+SD) Plasma Concentrations on Day 11 (SEDDS Formulation) TPV 1,200 mg + rtv 200 mg bid 240 TPV 300 mg + rtv 200 mg bid 220 TPV 1,200 mg bid 200 180 160 140 TPV Concentration (µM) 120 100 80 60 40 Target Cmin 20 0 7 0 1 2 3 4 5 6 8 9 10 11 12 Time (h)
PharmacokineticsConclusions • All doses of TPV/rtv (except 250/200) had median Cmin >20 µM • TPV induction of P450 3A4 was fully reversed by rtv co-administration • rtv 200 provided more consistent P450 inhibition regardless of TPV dose
ARV Naïve PatientsStudy Design • HIV-1 RNA 5,000 copies/mL • CD4 count 50 cells/mm3 • Treatment arms: • TPV 1200mg (SEDDS) bid • TPV 300 mg (SEDDS) + rtv 200 mg bid • TPV 1200 mg (SEDDS) + rtv 200 mg bid
ARV Naïve PatientsMean Changes in Viral Load Day on Therapy 0 3 5 8 11 15 -0.5 -0.77 log HIV-1 RNA (log10 copies/mL) -1 -1.44 log -1.5 -1.63 log -2 TPV 1200 mg bid TPV 300 mg bid + rtv 200 mg bid TPV 1200 mg bid + rtv 200 mg bid
Multiple PI FailuresStudy Design • Open-label, parallel groups • HIV-1+, multi-PI–experienced, NNRTI-naive adults • History of 2 or more PI-containing regimens • No wash-out period • No genotype or phenotype eligibility criteria • Primary endpoint • Mean plasma HIV-1 RNA reduction at 48 weeks
Multiple PI FailuresBaseline Values Low Dose High Dose 19 Number of subjects 22 4.46 (3.68–5.47) Plasma HIV-1 RNA(log10 copies/mL) 4.51 (3.87–5.21) CD4+ T cell count(cells/mm3) 314 (38–1067) 290 (41–610)
Low Dose High Dose Total Multiple PI FailuresPrior PI Experience 95% 100 93% 91% 80 68% 63% 61% Percent Prior Experience (N = 41) 56% 55% 60 53% 50% 44% 40 32% 20 0 IDV SQV NFV RTV
Multiple PI FailuresDosing Low Dose High Dose TPV HFC 1200 mg bid + rtv 100 mg bid TPV HFC 2400 mg bid + rtv 200 mg bid TPV SEDDS 500 mg bid + rtv 100 mg bid TPV SEDDS 1000 mg bid + rtv 100 mg bid + EFV 600 mg qd + 1 new NRTI + EFV 600 mg qd + 1 new NRTI Most patients initially took TPV 300 mg (HFC), then switched to TPV 250 mg soft-gel capsules (SEDDS) when these became available. 7/41 received SEDDS alone.
Multiple PI FailuresViral Load Reduction: BLQ<400 100 93.8% 78.9% 80 78.6% 60 Percent BLQ 50.0% 40 Low Dose, ITT-MCF Low Dose, AT-OC 20 High Dose, ITT-MCF High Dose, AT-OC 0 0 Weeks 4 8 16 24 48 Number of patients below detection 10 14 15 15 15 10 14 15 15 15 8 12 13 11 11 8 12 13 11 11
Multiple PI FailuresConclusions • TPV 500/100 and 1000/100 effectively suppressed VL in multiple-PI–experienced patients at 48 weeks • Patients taking 1000/100 had a higher incidence of adverse events, considered undesirable for chronic administration • The primary AEs seen for both doses were GI • SEDDS formulation was better tolerated than the HFC formulation
ARV Naïve Patients (1182.3)Adverse Events TPV 1200 mg TPV 300 mg TPV 1200 mg +rtv 200 mg +rtv 200 mg N=10 N=10 N=11 n (%) n (%) n (%) 1 (10%) 3 (30%) 0 (0%) Fatigue 6 (60%) 3 (30%) 7 (64%) Diarrhea 1 (10%) 0 (0%) 6 (54%) Nausea 1 (10%) 1 (10%) 2 (18%) Vomiting
Multiple PI Failure (1182.2)Most Common Adverse Events Gastrointestinal Diarrhea 59% (15/24 Grade 1) Nausea 31% Vomiting 17% Non-gastrointestinal Headache 39% Fatigue 29% Dizziness 27% Abnormal 27% dreams Insomnia 24% NB. Not all these AEs were considered TPV-related
Multiple PI Failure (1182.2)Laboratory Abnormalities Low Dose High Dose GGT, n (%) 6 (31.6) 4 (18.2) ALT 2 (10.5) 5 (22.7) AST 0 3 (13.6) TG 4 (21.1) 4 (18.2) Cholesterol 2 (10.5) 2 (9.1)
TipranavirConclusions • Co-administration with low dose rtv substantially enhances PK • BID dosing with rtv 100/200 achieves target Cmin • TPV induction on CYP450 is neutralized by rtv • Promising efficacy in PI failure patients • TPV/rtv is generally well tolerated- GI AEs are DAIDS Grade 1 to 2, self limited, or controllable with OTC medications