Clinical Aspects of Treatment with Tipranavir

Dr Kevin CurryBoehringer 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

• 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

Tipranavir Profile

• 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 PatientsMean (+SD) Plasma Concentrations on Day 11 (SEDDS Formulation)

Time (h)

TP

V C

once

ntra

tion

(µM

)

0

40

60

80

100

120

140

180

200

240

220

160

20

0 1 2 3 4 5 6 7 8 9 10 11 12

TPV 1,200 mg + rtv 200 mg bidTPV 300 mg + rtv 200 mg bidTPV 1,200 mg bid

Target Cmin

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

Studies in ARV Naïve PatientsBI 1182.3

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

-2

-1.5

-1

-0.5

03 5 8 11 15

TPV 1200 mg bid

TPV 300 mg bid + rtv 200 mg bid

TPV 1200 mg bid + rtv 200 mg bid

Day on Therapy

HIV

-1 R

NA

(lo

g1

0 co

pie

s/m

L)

-1.44 log

-1.63 log

-0.77 log

ARV Naïve PatientsMean Changes in Viral Load

Studies in Multiple PI FailureBI 1182.2

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

Plasma HIV-1 RNA(log10 copies/mL)

CD4+ T cell count(cells/mm3)

4.51(3.87–5.21)

314(38–1067)

4.46(3.68–5.47)

290(41–610)

Low Dose High Dose

Number of subjects 19 22

Multiple PI FailuresBaseline Values

32%

95%

53%

63%55%

91%

68%

50%44%

93%

61%56%

0

20

40

60

80

100

IDV SQV NFV RTV

Per

cen

t P

rio

r E

xper

ien

ce (

N =

41)

Low Dose High Dose Total

Multiple PI FailuresPrior PI Experience

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

+ EFV 600 mg qd+ 1 new NRTI

TPV SEDDS 1000 mg bid+ rtv 100 mg bid

+ 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 FailuresDosing

Low Dose, ITT-MCF

High Dose, ITT-MCFLow Dose, AT-OC

High Dose, AT-OC

0

20

40

60

80

100

4 8 16 24 48

Per

cent

BLQ

93.8%

78.9%78.6%

50.0%

0Number of patients below detection

10 14 15 15 1510 14 15 15 158 12 13 11 118 12 13 11 11

Weeks

Multiple PI FailuresViral Load Reduction: BLQ<400

• 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

Multiple PI FailuresConclusions

Adverse Event and Laboratory Profiles

TPV 1200 mg

N=10

TPV 300 mg+rtv 200 mg

N=10

TPV 1200 mg+rtv 200 mg

N=11

n (%) n (%) n (%)

Fatigue 1 (10%) 3 (30%) 0 (0%)

Diarrhea 6 (60%) 3 (30%) 7 (64%)

Nausea 1 (10%) 0 (0%) 6 (54%)

Vomiting 1 (10%) 1 (10%) 2 (18%)

ARV Naïve Patients (1182.3) Adverse Events

Gastrointestinal

Diarrhea59% (15/24 Grade

1)

Nausea 31%

Vomiting17%

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) Most Common Adverse Events

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)

Multiple PI Failure (1182.2) Laboratory Abnormalities

Tipranavir Conclusions

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