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BACKGROUND
Kaletra ™ (formerly known as ABT-378/r, lopinavir/ritonavir)
is a novel HIV protease inhibitor (PI) that has shown significant antiviral
activity and tolerability in clinical trials to date.
Lopinavir is co-formulated with
ritonavir, an inhibitor of cytochrome P450 3A. It is exquisitely sensitive to
pharmacokinetic enhancement by Ritonavir, resulting in substantially increased
lopinavir drug exposure, even at low ritonavir doses. At the dosage selected for
phase III clinical trials in adults, 400 mg lopinavir/100 mg ritonavir BID
capsules, ritonavir concentrations are below those required for antiviral
activity. 1 The mean lopinavir C trough /EC 50 ratio for wild-type HIV is
75 when dosed at 400/100 mg BID, potentially providing a pharmacologic
barrier to the emergence of viral resistance and activity against resistant
virus. 1 In contrast, the IQs for currently available Pls whether dosed as
single PIs or in conjunction with ritonavir, range from 1-26 (Figure 1), based
on the EC 50 values determined in the presence of 50% human serum. 2 C
trough values in HIV+ patients for currently available PIs are derived from
published sources including package inserts. 3-14
The efficacy and safety of
Kaletra™ are
currently being studied in HIV-infected adult patients, both
antiretroviral-naïve and PI-experienced. Study M98-940 is a Phase I/II,
open-label study of coformulated Kaletra™ (liquid)
at two doses in combination with reverse transcriptase inhibitors in
treatment-naïve and -experienced pediatric subjects.
Figure
1. C trough /EC 50 Ratio
(Inhibitory Quotient) for PIs Given Alone or with RTV*
* Contribution of RTV to
antiviral activity not included; regimens shown are those where data in
HIV-infected patients are available; EC 50 values adjusted for protein binding.
METHODS
Evaluate the safety, tolerability
and antiviral activity of Kaletra ™ (liquid formulation) in HIV-infected
children.
Entry Criteria
Age: between 3 months
and 12 years
Plasma HIV RNA >400
copies/mL
No prior NNRTI therapy
Study Design and Analysis
One hundred
antiretroviral-naïve and -experienced pediatric subjects were randomized to
receive one of two dosage levels of Kaletra ™ (230/57.5 mg/m 2 Q12H or
300/75 mg/m 2 Q12H) selected to approximate the adult drug exposure at 400/100
mg BID.
Subjects were defined as
antiretroviral-naïve if they had received 3 months of prior antiretroviral
therapy or 1 week of treatment with 3TC. Subjects were defined as
antiretroviral-experienced if they received >3 months of prior antiretroviral
therapy or >1 week of treatment with 3TC.
In addition to Kaletra ™,
naïve subjects received treatment with d4T and 3TC and experienced subjects
received treatment with nevirapine and 1 or 2 NRTIs of the investigator’s
choice.
All subjects were
switched to a dose of Kaletra ™ 300/75 mg/m 2 following an analysis of
safety/tolerability, efficacy and Week 3 pharmacokinetics.
Figure 2.
RESULTS
Table 1.
Baseline Characteristics
Treatment Experience and
Pharmacokinetics
Of the 56 experienced
subjects enrolled, 32 were NRTI experienced and 24 were protease inhibitor
experienced.
88% of the PI experienced
subjects had received ritonavir (standard dose) and 29% had received multiple
PIs.
There was no
statistically significant effect of age on the pharmacokinetic parameters of
lopinavir. From the analysis of covariance (ANCOVA) for age effect p=0.2 for AUC
and p=0.7 for C trough .
Subject Disposition
Of the 100 subjects
enrolled in the study, two subjects had discontinued as of Week 48 (Table 2).
Safety
There were few adverse
events of at least moderate severity and of probable or possible relationship
to study drug or grade 3/4 laboratory abnormalities at 48 weeks (Tables 3 and
4).
Viral Load Suppression to
<400 Copies/mL at 48 Weeks
The proportion of
subjects with viral load less than 400 (less than 50) copies at Week 48 was
84% (71%) for naïve subjects and 75% (63%) for experienced subjects by the
Intent-to-Treat method of analysis.
In general, the
proportion of subjects below 400 copies was higher in the naïve group than in
the PI-experienced group beginning at Week 12 and beyond (Figure 3).
Figure 3. HIV
RNA <400 Copies/mL (Intent-to-Treat)
Table 5. Mean
Change from Baseline in HIV RNA Levels (log copies/mL)
 
Figure 4. HIV
RNA <400 Copies/mL (Intent-to-Treat) Stratified by Baseline Viral Load
CD4 Response
Mean CD4 cell count
increase from baseline was 404 cells for naive subjects and 238 cells for
experienced subjects by Week 48.
Figure 5. % CD4
Response
CONCLUSIONS
- There was one discontinuation
related to study drugs through 48 weeks.
- There were few adverse events
of at least moderate severity and of probable or possible relationship to
study drugs or grade 3/4 laboratory abnormalities at 48 weeks.
- 84% of treatment-naive
subjects and 75% of treatment-experienced subjects were <400 copies/mL
HIV RNA at Week 48 by an Intent-to-Treat Analysis.
REFERENCES
- Bertz R, Lam W, Brun S, et al.
Multiple-dose pharmacokinetics (PK) of Kaletra ™ Ritonavir (Kaletra ™ )
in HIV+ subjects. 39th Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Francisco, USA, 1999, (abstract 0327).
- Kempf DJ, Molla A, Hsu A.
Protease inhibitors as anti-HIV agents. Antiretroviral Therapy, American
Society for Microbiology Press, E DeClerq, editor. In press.
- Ritonavir Package
Insert.
- Indinavir Package
Insert.
- Amprenavir Package insert.
- Nelfinavir Package Insert.
- Saquinavir (Fortavase) Package
Insert.
- Cohen C, et al. Potent and
convenient Fortovase ™ (SQV) SGC BID regimens in combination with 2
nucleosides or nelfinavir (NFV) plus 1 nucleoside in HIV-1 infected
patients. 12th World AIDS Conference, Geneva, Switzerland, 1998, (abstract
12314).
- Saag M, et al. Saquinavir
systemic exposure and safety on once daily administration of Fortovase ™
(Saquinavir) soft gel capsules (FTV) in combination with low-dose ritonavir.
39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San
Francisco, USA, 1999, (abstract 330).
- Shulman N, et al. Ritonavir
intensification in indinavir recipients with detectable HIV RNA levels. 7th
Conference on Retroviruses and Opportunistic Infections, San Francisco, USA
(abstract 534).
- Piscitelli S, et al. The
addition of a second protease inhibitor eliminates Amprenavir-Efavirenz drug
interactions and increases plasma Amprenavir concentrations. 7th Conference
on Retroviruses and Opportunistic Infections, San Francisco, USA (abstract
78).
- Mallolas J, et al. A
dose-finding study of once-daily Indinavir/Ritonavir plus Combivir ® in HIV
infected patients. First International Workshop on Clinical Pharmacology of
HIV Therapy, March 2000 (abstract 2.14).
- Flexner C, et al.
Steady-state pharmacokinetic interactions between ritonavir (RTV),
nelfinavir (NFV), and the nelfinavir active metabolite M8 (AG1402), 12th
World AIDS Conference, Geneva (abstract 42265).
- Cameron DW, et al. Ritonavir
and saquinavir combination therapy for the treatment of HIV infection. AIDS,
1999, 12(2) 213-224.
Poster 225
Kaletra ™ (ABT-378/ritonavir) in HIV-Infected Children at 48
Weeks
© 2000 Medical Advocates
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