• Lopinavir (LPV)

– Is a potent inhibitor of HIV-1 protease, with plasma protein binding-adjusted in vitro EC 50 approximately 10 times higher than that of ritonavir.

– Is rapidly and exclusively metabolized by CYP3A in vitro.

– Plasma concentrations in humans are unremarkable when administered alone.

– However, LPV mean trough concentration reached 78 times of protein binding-corrected-EC 50 for wild-type HIV when 400 mg of LPV is co-administered with 100 mg ritonavir BID in HIV-infected patients.

– Lopinavir is co-formulated with ritonavir at 4:1 ratio (133.3/33.3 mg lopinavir/ritonavir per capsule or 80/20 mg lopinavir/ritonavir per mL oral solution).

– Kaletra (LPV/r 400/100 mg BID) is recently approved for the treatment of HIV infection in the USA and Brazil.

• Ritonavir (RTV or r)

– Is metabolized by CYP3A and to a lesser extent by CYP2D6.

– Is a potent CYP3A inhibitor, with a Ki of 0.009 µg/mL for LPV.

– In HIV-therapy naïve subjects, 100 mg RTV bid in combination with 400 mg LPV BID yielded RTV plasma concentration <1/15 of that of LPV.

• Nevirapine (NVP)

– Is a non-nucleoside HIV reverse transcriptase inhibitor.

– Is metabolized by CYP2B6 and 3A.

– Is an enzyme inducer of hepatic cytrochrome P450 metabolic enzymes, leading to a mean decrease in indinavir and saquinavir steady-state AUC of 28% and 24%.

• No statistically significant pharmacokinetic interaction was observed in a previous Phase I, three parallel-arm study in healthy volunteers

– Three arms were NVP alone, Kaletra 400/100 mg BID alone, and Kaletra 400/100 mg BID + NVP, respectively.

– PK was assessed on Week 2 and 3.

– Steady state was reached by Day 14 for LPV and RTV.

– NVP PK parameters were similar to those reported in the literature.

– Concurrent administration of NVP did not significantly affect the PK of LPV and RTV.

• Interim analysis of Kaletra (400/100 vs. 400/200 mg BID) + NVP + NRTI showed excellent antiviral activity in single PI-experienced subjects in a Phase II study; plasma viral load was suppressed in 90% and 86% of subjects, respectively, after dosing for 72 weeks (on treatment). Limited PK data were obtained; with LPV and RTV concentrations not obviously different from treatment-naïve subjects who were treated with Kaletra + NRTIs without NVP.
  
  
• Thus, Kaletra + NRTI ± NVP was chosen for pediatric Phase I/II Study M98-940.

• To select an adult-equivalent Kaletra dose for pediatric patients based on tolerability, efficacy, and drug levels.
• To evaluate the safety and antiviral activity of the selected Kaletra dose when used in combination with reverse transcriptase inhibitos.

• 3 months to 12 years old, inclusive
• Plasma HIV RNA>300 copies/mL
• No opportunistic infection within the last 90 days
• Life expectancy > 12 months

• – Protease inhibitor and/or NRTI experienced
• – NNRTI-experienced were excluded

Full 12-hr week-3 PK were determined in a subset of 53 subjects, stratified according to age (2 years and 2-12 years) and prior anti-retroviral drug experiences With the exception of ddI, dosing was to be after a meal (within 30 minutes) and approximately 12 hr (±1 hr) from the previous evening dose

• < 20% of subjects experienced a Grade 3 or higher adverse event or laboratory abnormality
• > 75% of subjects experienced at least 0.5 log reduction in viral load in the first 3 weeks of dosing
• Central values for AUC and C min were within 80% and 130% of the average adult exposure

For the pharmacokinetic subset, plasma samples for PK study of LPV and RTV were collected at 0 hour (predose) and 2, 4, 6, 8 and 12 hours after the morning dose during the 12-hour PK evaluation.

For the non-pharmacokinetic subjects, trough (predose) plasma concentrations were to be determined on Day 22.

LPV and RTV plasma concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection.

The lower limits of quantitation for LPV and RTV were 5.0 and 1.0 ng/mL, respectively.

Conventional noncompartmental methods were used to calculate pharmacokinetic parameters.

An analysis of covariance (ANCOVA) was performed on elimination rate constant (b) and the logarithms of C min , C max , AUC and C trough to investigate the relationship between the pharmacokinetic parameters (for LPV and ritonavir) and age, regimen, gender, race, other appropriate variables.

The final ANCOVA model included effects for regimen, NVP co-administration and their corresponding two-way interaction, with age as a covariate.

Kaletra in combination with NRTIs with or without NVP is well tolerated in pediatric subjects, only one subject dropped out due to a study drug related adverse event after 48 weeks of dosing.

Percent of subjects with HIV RNA <400 copies/mL at 48 weeks (intent to treat):

• Antiretroviral naïve 84% (n=44)
• NRTI experienced 88% (n=32)
• PI experienced 58% (n=24)

• Age has no effect on LPV and RTV PK parameters (Figure 2).
• Concurrent administration of NVP significantly affect the pharmacokinetic parameters of LPV and RTV at steady state (Figure 3). 
• 300/75 mg/m² Kaletra + NVP + NRTIs and 230/57.5 mg/m² Kaletra + NRTIs (without NVP) provided LPV and RTV exposures similar to those observed in HIV-infected adults receiving 400/100 mg BID without NVP (Table 4 and Figures 4 and 5).

• No significant differences in efficacy or safety were noted between the two dose groups.
• No significant age effect (from 6 mo. to 12 yr.) in pharmacokinetics was observed.
• Thus, based on the initial assessment of preliminary PK, safety, and efficacy data, subjects receiving 230/57.5 mg/m² BID with or without NVP were switched to 300/75 mg/m² BID during study Days 82 to 141.
• The adverse event prevalence rates remained similar between naïve and treatment-experienced subjects in 230/57.5 mg/m² dose group after they were switched to the 300/75 mg/m² BID dose.
• However, final PK analysis found that NVP reduced plasma concentrations of LPV and RTV probably due to enzyme induction.

– The 300/75 mg/m² BID when co-dosed with NVP, and the 230/57.5 mg/m² BID without co-dosing with NVP, provide plasma concentrations which approximate those observed in adults receiving 400/100 mg BID without enzyme inducers (Tables 5 and 6).

• The final recommended Kaletra dose for pediatric patients is 230/57.5 mg/m² BID.
• However, when used with enzyme inducers such as NVP or efavirenz, 300/75 mg/m² BID should be considered in subjects when reduced susceptibility to LPV is clinically suspected (by treatment history or laboratory evidence).

• Kaletra is well tolerated in HIV-infected pediatric subjects with no Kaletra discontinuations to date and only one non-study drug related discontinuation.
• Viral suppression is observed in treatment-naive and experienced subjects; however, viral suppression is better in treatment-naïve children.
• The results of this study indicate that nevirapine, an enzyme inducer, reduced plasma concentrations of lopinavir and ritonavir.
• The recommended pediatric Kaletra dose is 230/57.5 mg/m² BID. When used with enzyme inducers such as nevirapine or efavirenz, 300/75 mg/m2 BID should be considered when reduced susceptibility to lopinavir is clinically suspected.

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Kaletra Conference Data

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  Assessment of Pharmacokinetic Interactions Between 
Kaletra  (lopinavir/ritonavir or ABT-378/r) and Nevirapine in Pediatric Subjects   

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