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2 Kaletra High-Dose Regimens in PI-Experienced: Pk and short-term viral response
Reported by Jules Levin
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"Steady-State Pharmacokinetics and Short-Term Virologic Response of Two Lopinavir/ritonavir (LPV/r) High-Dose Regimens in Multiple Antiretroviral-Experienced Subjects (Study 049)"
Second IAS Conference on HIV Pathogenesis and Treatment, Paris, France, 13-16 July 2003. Poster #843
In patients failing multiple antiretroviral regimens with multiple protease inhibitor experience, high-level drug resistance is likely including to protease inhibitors. Increased doses of Lopinavir/ritonavir (Kaletra) may be needed to achieve higher lopinavir (LPV) concentrations and overcome LPV resistance. The purpose of this study was to assess the pharmacokinetics (PK) of two high-dose LPV/r regimens. Summary: 31 multiple PI-experienced patients with <200 CD4s received 1 of 2 high-dose Kaletra regimens—either LPV/r 400/300 mg twice daily or 667/167 mg twice daily (each regimen was 5 capsules). The standard Kaletra (lopinavir/r) dose regimen is 400/100 mg twice daily. After 4 weeks the viral load reduction was about the same in both groups, -1.2 to –1.5 log. The 667/167 regimen increased lopinavir blood levels 73% to 88%. The 400/300 regimen increased lopinavir levels 47% to 59%. Ritonavir blood levels were 3 times higher using the 400/300 regimen compared to the 667/167 regimen and 6 times higher than using the standard 400/100 Kaletra regimen. Patients will continue to be studied for 1 year of treatment for pharmacokinetic and pharmacodynamic relationships and tolerability.
Multiple PI and NNRTI-experienced HIV+ subjects were randomized to receive one of two twice daily (BID) high-dose LPV/r regimens with food; NRTIs (2-3) were selected by the care provider. This was a multiple-dose, open-label, multiple-center, non-fasting study in 36 HIV-infected individuals who had:
--multiple PI-experience
--NNRTI experience
--no evidence of acute illness
--HIV viral load >1000 copies/ml
--CD4 count <200
Three patients discontinued from the study prior to week 3 due to adverse events: fever, nausea and vomiting, asthenia (weakness) & vomiting & dizziness.
PK samples were obtained from 33 subjects; 2 receiving a concurrent NNRTI were excluded from the analysis. LPV/r 667/167 mg was given as 5x133/33 mg LPV/r caps BID (N=18), and LPV/r 400/300 mg was given as 3x133/33 mg LPV/r caps + 2x100 mg ritonavir (RTV) caps BID (N=13).
Plasma PK of LPV and RTV was measured over a 12-hour dosing interval after 3 weeks. PK parameters were log transformed and compared using ANCOVA.
Results from a previous Study 056 in which ART-naïve subjects (n=19) received LPV/r 400/100 mg twice daily with NERTIs, (d4T and 3TC twice daily for 3 weeks served as historical controls. Median viral load was 45,000 copies/ml. Median CD4 count was 96. Median lopinavir phenotypic resistance (fold-change from wt-HIV) was 3.6.
PATIENT CHARACTERISTICS for High-Dose Study
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LPV/r 400/300mg BID
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LPV/r 667/167 BID
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Historical LPV/r 400/100mg BID
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N=13
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N=18
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N=19
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Gender
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Male
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10
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15
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13
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Female
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3
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3
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9
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Age
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40
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42
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34
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Wt
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162
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166
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165
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Ht (cm)
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172
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172
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171
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Race
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caucasian
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11
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11
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10
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Black
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0
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7
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9
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Hispanic
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2
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0
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0
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LPV IQ was calculated as C-trough/wt-IC50 based on protein binding-adjusted IC50 of 0.07 ug/ml. Actual IQ was calculated as C-trough/(phenotype fold-change*0.07 ug/ml.
Results
LPV/r 667/167 vs. 400/300 mg BID produced LPV mean ± SD
--Cmax of 16.2 ± 4.5 vs. 14.5 ± 5.5 µg/mL (p=0.25)
--AUC-12 hr of 165 ± 54 vs. 145 ± 59 µg•h/mL (p=0.3)
--C trough of 12.0 ± 4.5 vs. 11.6 ± 5.2 µg/mL (p=0.5).
RTV C max and AUC were higher (p<0.01) in the 400/300 vs. 667/167 mg regimen by 3- and 2.7-fold, respectively.
Compared to historical data for LPV/r 400/100 mg BID + NRTIs in HIV+ subjects (N=19), LPV C max, AUC and C trough from ANCOVA were 73, 88 and 73% higher for 667/167 mg, and 47, 59 and 56% higher for 400/300 mg, respectively (p<0.01 for all).
RTV C max and AUC were 6-fold higher after 400/300 mg and 2-fold higher after 667/167 mg than with LPV/r 400/100 mg (p<0.01). Median viral load (VL) change from baseline to Wk 4 was -1.2 log 10 c/mL.
Lopinavir Mean PK Parameters
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400/300
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667/167
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400/100
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Cmax (ug/ml)
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14.5
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16.2
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9.8
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AUC-12 (ug*h/ml)
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144.9
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164.5
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92.6
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Cmin (ug/ml)
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9.9
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10.1
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5.5
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Ctrough (ug/ml)
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11.6
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12.0
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7.1
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IQ (wt-HIV IC50)
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173
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164
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98.1
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Phenotype
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3.9
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5.0
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-
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IQ (actual-HIV IC50)
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70.7
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27.0
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-
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The 4-week virologic response: the overall median viral load change from baseline to week 4 was –1.2 log in the 400/300 regimen and –1.5 log in the 667/167 regimen. The viral changes were similar between the LPV/r dosing regimens.
The study authors concluded:
--Increasing the number of LPV/r caps to 5 or adding 2 additional RTV capsules to the standard dose of Kaletra results in relatively similar increases in LPV exposure.
--LPV/r 667/167 mg (5 caps) BID regimen results in a 73% increase in Ctrough, 88% increase in AUC, and 73% increase in Cmax compared to the approved dose of LPV/r 400/100mg BID
--LPV/r 400/300 mg BID results in increases in Ctrough of 56%, increase in AUC of 59%, and Cmax of 47%
--Adding RTV 200 mg (400/300 regimen) increases RTV exposure by about 3-fold compared to increasing LPV/r by 267/67 mg. RTV AUC was 4.6 ug/ml in the 400/100 mg standard dose compared to 9.6 ug/ml using the 667/167 regimen and 28.1 ug/ml using the 400/300 regimen.
--The two high-dose LPV/r regimens produced a short-term median decrease in VL of >1 log 10 c/mL in these heavily ARV-experienced subjects.
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