Transcript Pharmacokinetics of Saquinavir hard gel (Invirase)

The 4th International
Workshop on Clinical
Pharmacology of HIV
Therapy
8.11
Pharmacokinetics of Saquinavir hard gel (Invirase) when
combined with Atazanavir
D
1
Prelutsky ,
P
2
Salvato ,
R
3
Falcon
1. Washington University School of Medicine, St. Louis, MO, USA; 2. Diversified Medical Practices , Houston, TX, USA; 3. Roche Laboratories, Nutley, NJ, USA
Table 1: Baseline Characteristics
Abstract
The use of protease inhibitors (PI) has evolved since their introduction.
Commonly, protease inhibitors are pharmacokinetically boosted by
coadministration with a cytochrome p450 cyp 3A4 inhibitor like Ritonavir.
This combination leads to increases in PI exposure and T½, allowing for
more effective therapy with more convenient dosing.
Ritonavir, while an effective boosting agent, has been associated with side
effects such as hyperlipidemias and GI intolerance. Atazanavir is a new
PI which is currently under review for market approval by health
authorities. Atazanavir has shown the ability to boost Saquinavir soft gel
(Fortovase) levels 5 to 6-fold when coadministered in healthy volunteers 3.
O’Mara demonstrated Cmax, AUC and Cmin levels of 6589ng/ml, 30807
ng●hr/ml and 92ng/ml for healthy subjects taking Fortovase 1600mg with
Atazanavir 400mg both dosed once daily. No data has ben published on
the interaction of Saquinavir hard gel (Invirase) with Atazanavir or the
interaction of Atazanavir with Saquinavir in HIV-infected patients. When
boosting with Ritonavir, previous studies 1,2 have demonstrated similar
Mean Cmin values when Saquinavir hard gel (Invirase) or Saquinavir soft
gel (Fortovase) is given. This has lead to increased interest in Invirase as
the preferred formulation due to better GI tolerability, smaller tablet size
and easier storage.
Patient
gender
Age (years)
CD4 (cells/ml)
HIV-RNA (copies/ml)
1
Male
40
244
228,000
2
Male
41
54
477,000
3
Male
42
64
> 750,000
Patient
ATZ 400mg qd & SQV
600mg tid
ATZ 400 & SQV 1600 mg
qd
4
Male
41
125
> 750,000
7
180 ng/ml
143 ng/ml
5
Male
42
23
174,000
8
160 ng/ml
97 ng/ml
9
89 ng/ml
298 ng/ml
10
197 ng/ml
not available
11
89 ng/ml
23 ng/ml **
12
Not drawn
74 ng/ml
Median 160 ng/ml
Mean 143 ng/ml
Median 120 ng/ml
Mean 153 ng/ml
6
Houston
Background
Baseline at initiation of ATV
St. Louis
Background: Previous studies have demonstrated similar Mean Cmin
values when Invirase or SQV soft gel (Fortovase) is boosted with
Ritonavir 1,2. This has lead to increased interest in Invirase as the
preferred formulation due to better tolerability. The pharmacokinetics of
Atazanavir (ATV) with Fortovase have recently been described in
healthy volunteers, showing a significant boosting effect of Atazanavir on
Fortovase 3. Little is known about the pharmacokinetics of Atazanavir
combined with Invirase in HIV-Infected adults.
Methods: We are reporting a multi-center, observational study of 12 HIV
infected patients taking varying doses of Invirase with 400mg of
Atazanavir once daily with food. Doses of Invirase included 600mg TID,
1200mg QD, and 1600mg QD.
Results: N=12, all male, mean age was 42 years, all prior antiretroviral
treatment experienced. Mean CD4 88 (range zero-244). The Mean and
Median Cmin levels for patients taking 1200mg Invirase QD were 309 and
250ng/ml respectively. With a dose of Invirase 600mg TID, we observed
143 and 160ng/ml for Mean and Median Cmin values. Patients receiving
1600mg Invirase QD had Mean and Median Cmin values of 153 and
120ng/ml.
Conclusions: In this limited observational study, Invirase, when given
with Atazanavir, resulted in Cmin levels which indicate that Atazanavir acts
as a significant pharmacokinetic booster of Invirase. 7 of 11 patients
achieved a Cmin level above the EC50 of SQV of 50ng/ml. Formal PK
studies will need to evaluate the optimal dose for the combination of
Atazanavir with Saquinavir hard gel (Invirase).
Male
52
189
Table 4: Saquinavir-hgc (Invirase) pre dose Cmin
levels
9,740
7
Male
37
18
> 750,000
8
Male
44
145
162,000
9
Male
41
70
38,500
10
Male
52
28
540,000
11
Male
41
96
260,000
12
Male
36
0
531,250
Due to the paucity of data of this combination therapy in HIV infected individuals,
random Cmin Saquinavir levels were obtained in 4 patients at the St. Louis site .
Significant inter-patient variability was observed. Adherence was assessed by patient
interview and felt to be appropriate.
**: drawn late at 29 hours post dose. Value censored for statistical analysis
Limitations
While the results of this observational study give an initial impression of the
interaction of Atazanavir with Saquinavir hard gel (Invirase), drug levels
obtained in routine patient care settings may be influenced by multiple factors
including adherence, incorrect timing of dose and lack of standardized food
intake. In addition the levels reported here were obtained from more than one
laboratory.
Table 2: Saquinavir-hgc (Invirase) random pre-dose Cmin levels
Conclusions
Patient
ATZ400 & SQV1200 mg qd
1
700 ng/ml
2
300 ng/ml
3
200 ng/ml
4
38 ng/ml
 In this limited observational study, Invirase, when given with Atazanavir,
Median 250 ng/ml
Mean 309 ng/ml
In follow up, some patients were evaluated more comprehensively with Saquinavir Cmax
levels drawn 3 hours after an observed dose, followed by Cmin levels 24 hours after the
observed dose.
Table 3: Patients with Cmin and Cmax values during directly
observed (DOT) dosing cycle
Methods
•Multi-center, observational study of 12 HIV infected patients, taking
varying doses of Invirase with 400mg of Atazanavir once daily with
food, along with nucleoside reverse transcriptase inhibitors. Patients
on concomitant NNRTI therapy were excluded.
•Drug levels were obtained as part of routine medical care in HIV
specialized care facilities in St. Louis and Houston, USA.
•All patients had been on therapy at least 14 days, ensuring levels
were obtained at steady state.
•In some patients levels were repeated.
•For some levels, the medication dose was taken as observed
therapy (DOT), followed by 3 hour post dose Cmax and 24 hour post
dose Cmin levels.
•The St. Louis site used Quest diagnostics and Specialty labs.
•The Houston site used TDM labs
At the Houston site of this observational study, several patients had initiated
treatment with Atazanavir 400mg qd & Saquinavir hard gel (Invirase) 600mg
tid. Cmin Saquinavir levels were assessed. For patient convenience the dose of
Saquinavir was switched to 1600mg once daily and Cmin levels were repeated
after at least 14 days on the new therapy.
Patient
Dose
Cmax, drawn 3 hours
post DOT dose
Cmin, dawn 24 hours
post DOT dose
1
ATZ 400 & SQV1200
mg qd
630 ng/ml
<25 ng/ml*
2
ATZ 400 & SQV1200
mg qd
2200 ng/ml
70 ng/ml
3
ATZ 400 & SQV1200
mg qd
547 ng/ml
348 ng/ml
5
ATZ 400 & SQV1200
mg qd
50 ng/ml
60 ng/ml
6
ATZ 400 & SQV1600
mg qd
993 ng/ml
45 ng/ml
Median 630 ng/ml
Mean 884 ng/ml
Median 60 ng/ml
Mean 105 ng/ml
*: value counted as 0 ng/ml for statistical analysis
resulted in Cmin levels, which indicate that Atazanavir acts as a significant
pharmacokinetic booster of Invirase.
 7 of 11 patients achieved a Cmin level above the EC50 for SQV of 50ng/ml.
Formal PK studies are needed to further characterize the interaction between
Invirase and Atazanavir.
 Does the boosting effect of Atazanavir on Saquinavir hard gel (Invirase) differ
from the boosting effect on Saquinavir soft gel (Fortovase)?
– Our data does not allow for a direct answer of this question. The
interaction of Atazanavir and Fortovase was evaluated in formal PK in
healthy individuals 3, while our data with Invirase was obtained in routine
care settings in HIV-infected individuals.
– Nevertheless the Saquinavir levels achieved in this cohort are
significantly higher than those achieved by Invirase alone, supporting the
claim of Atazanavir being a significant booster for Invirase.
 Formal PK studies will need to evaluate the optimal dose for the combination
of Atazanavir with Saquinavir hard gel (Invirase)
References
1. The 9th Conference on Retroviruses and Opportunistic Infections
(Abstract S29e). Seattle. Feb 24-28, 2002.
2. The 3rd International Workshop on Clinical Pharmacology of HIV Therapy
(Abstract MoPp B2007). Washington DC. April 2002.
3. The 7th Conference on Retroviruses and Opportunistic Infections
(Abstract 504). San Francisco, CA. Jan 30 - Feb 2, 2000.
Contact
Ron Falcon MD
Roche Laboratories Inc.
340 Kingsland Street
Nutley, NJ 07110
USA
E-Mail: [email protected]