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High Dose Kaletra in Highly Experienced Patients
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Reported by Jules Levin
11th Conference on Retrovirus and Opportunistic Infections
February 8-11, 2004, San Francisco, CA
"Lopinavir Inhibitory Quotient Predicts Virologic Response in Highly Antiretroviral-experienced Patients Receiving High-dose Lopinavir/Ritonavir"
R Bertz*1, J Li1, M King1, D Kempf1, D Podzamczer2, C Flexner3, C Katlama4, D V Havlir5, S Letendre6, J Eron7, L Weiss8, J Gatell9, A Simon4, K Robinson1, and S Brun1
1Abbott Labs., Abbott Park, IL, USA; 2Hosp. de Bellvitge, Barcelona, Spain; 3Johns Hopkins Univ. Sch. of Med., Baltimore, MD, USA; 4Hosp. de la Pitie-Salpetriere, Paris, France; 5Univ. of California, San Francisco, USA; 6Univ. of California, San Diego, USA; 7Univ. of North Carolina at Chapel Hill, USA; 8Hosp. Europeen George Pompidou, Paris, France; and 9Hosp. Clin., Barcelona, Spain
SUMMARY by Jules Levin: Many patients have drug resistance to protease inhibitors. Kaletra is a potent PI and is effective for many patients with PI resistance. But many patients already have extensive PI resistance and some degree of resistance to Kaletra. Abbott Pharmaceuticals, the developer of Kaletra, has been exploring the use of high-doses of Kaletra to examine the effect in suppressing HIV in highly pre-treated patients with extensive resistance to protease inhibitors and Kaletra. The purpose of looking at higher doses of Kaletra is to see if using the high-dose therapy for highly drug resistant patients will be successful in suppressing HIV tondetectable and tolerable. The patients receiving one of two high dose Kaletra regimens (667/167 mg LPV/r or 400/300 mg LPV/r, twice daily) in this small proof of concept study had these characteristics: HIV for 8.3 yrs; number of active NRTIs, 1; had 3-5 Kaletra drug mutations; LPV fold wt-IC50 (phenotype): 4.5 (0.6-273, min-max); had HIV viral load of 4.7 log (50,000 copies/ml); average CD4 count of 91. The pharmacokinetics results are reviewed below. Both regimens were similar in reducing viral load –1.39 log after 48 weeks. 83% of patients had >1 log viral load reduction. The 667/167 mg regimen appeared to have better tolerability (diarrhea, vomiting, triglycerides), see details below. The authors concluded: In (1) LPV IQ Ctrough was a significant predictor of antiviral response in these multiple PI and NNRTI experienced patients; (2) The number of active NRTIs was also a significant predictor of antiviral response in both analyses; (3) Higher doses of LPV/r may provide LPV concentrations sufficient to overcome certain degrees of reduced LPV phenotypic susceptibility, resulting in a significant treatment effect. 48-week safety & antiviral effects data is expected to be presented at IAS Bangkok 2004.
Rick Bertz presented this oral talk at the 11th Retrovirus Conference (San Francisco, Feb 8-11, 2004).
Lopinavir (LPV) is a protease inhibitor that is co-formulated in one capsule with low-dose ritonavir which enhances LPV pharmacokinetics (drug levels in the blood). At the Kaletra (LPV/r) 400/100 mg bid (twice daily) patient dose, LPV Ctrough (lowest drug level during dosing period) exceeds protein-adjusted IC50 for wild-type (wt) HIV by >76-fold (inhibitory quotient (IQ) or Ctrough/IC50=75). IQ is a ratio of the lowest drug level (Ctrough) andhow much more it is than the amount of drug needed to suppress 50% of virus replication (IC50), which is commonly used by researchers to evaluate the levels of drug of a therapy andtherefore itspotency and effectivesness.
LPV concentrations achieved with standard patient dose have resulted in significant antiviral efficacy and durable response, particularly in patients with previous ART experience.
However, high level drug resistance can occur in patients failing ART regimens. In a previous study in multiple PI-experienced and NNRTI-naïve patients, a relationship between LPV IQ and antiviral response was demonstrated using clinical doses of LPV/r (Hsu A, et al AAC 2003 47(1): 350-9).
Increased doses of LPV/r may be needed to achieve higher LPV concentrations and overcome LPV resistance and resistance to other protease inhibitors.
The objective of this study was to assess predictors of antiviral response in multiple PI and NNRTI experienced patients receiving high-dose LPV/r.
STUDY 049 DESIGN
This was an open-label multi-center study in HIV-infected subjects (n=36) who were multipli PI & NNRTI experienced and had >1000 copies/ml HIV viral load. PK and antiviral effects results from this study were previously reported.
36 were randomized to and received 1 of 2 twice daily high-dose LPV/r regimens with food: 667/167 mg (5 x 133/33 mg LPV/r caps, n = 19) or 400/300 mg (3 x 133/33 mg LPV/r caps + 2 x 100 mg ritonavir caps, n = 14). NRTI (2 to 3) were selected by the care provider. Concurrent NRTIs: ddI (n=21); 3TC (n=15); d4T (n=15); abacavir (n=13); tenofovir (n=10); AZT (n=5).
3 subjects discontinued prior to PK assessment. Plasma samples for LPV pharmacokinetics were obtained over a 12-hour dosing interval at week 3.
To assess antiviral activity, time-averaged difference from baseline for HIV RNA through week 48 (TAD) and demonstration of HIV RNA <400 copies/mL were quantified. Variables explored for association included demographics, baseline disease characteristics, resistance, treatment history, active agents in regimen, LPV pharmacokinetics (Cmax, AUC, Ctrough, and Cmin), and LPV inhibitory quotient (Ctrough/individual protein binding-adjusted IC50 for HIV) using linear and logistic regression.
NATAP REPORT OF RESULTS FROM THIS STUDY REPORTED AT IAS (Intl AIDS Conference) PARIS, JULY 2003
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).
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.
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.
In table immediately below, gray line is 667/167 dose, blue line is 400/300, and black line is 400/100.
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BACK TO CROI 2004 REPORT FROM ABBOTT
Bertz reported a graph of the steady state lopinavir mean (SD) concentration-time profiles which showed that over 12 hour dosing period both high-dose LPV/r regimens appeared significantly above drug levels of standard dose of LPV/r.
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Comparison
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Parameter
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PE
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90% CI
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400/300 vs 667/167
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AUC12
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0.85
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0.63 -1.13
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Ctrough
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0.91
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0.69 –1.19
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400/300 vs 400/100
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Ctrough
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1.56
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1.19 –2.04
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667/167 vs 400/100
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Ctrough
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1.73
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1.35 –2.21
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STUDY 049: PK/PD Analysis Methods
All patients were analyzed with post-baseline HIV RNA and pk data (n=33)
ENDPOINTS AND ANALYSIS:
--average HIV RNA change from baseline through 48 weeks ("AAUCMB", "TAD", or "DAVG" analysis) – linear regression with forward stepwise selection
--proportion achieving HIV RNA <400 copies/ml – logistic regression with forward stepwise selection
INDEPENDENT VARIABLES:
Base characteristics: age, gender, race, weight, body mass index (BMI), CD4 count, HIV RNA, time since diagnosis
Previous and concurrent ARV use: treatment group; no of previous NRTIs, NNRTIs, and protease inhibitors; concurrent tenofovir use
Viral susceptibility: LPV fold change from wt-IC50 (phenotype), genotype (no of LPV mutations), no of active NRTIs
Pharmacokinetics: LPV/Cmin, Ctrough, Cmax, AUC
Lopinavir Inhibitory Quotient: LPV IQ=Ctrough/HIV IC50
STUDY 049: SELECTED BASELINE CHARACTERISTICS AND PK PARAMETERS
(median)
Age: 42 yrs
Weight: 69 kg
BMI: 24 kg/m2
CD4 count: 91
HIV RNA: 4.7 log
LPV fold wt-IC50 (phenotype): 4.5 (0.6-273, min-max)
No of LPV mutations (LPV score): 5
No of LPV mutations (ATU set): 3
Previous PIs: 4
Time since diagnosis: 8.3 yrs
No of active NRTIs: 1
LPV Ctrough: 11.4 ug/mL (2.5-21.9)
LPV Cmin: 9.2 ug/mL (1.8-17.0)
LPV Cmax: 15.5 ug/mL (5.5-23.1)
LPV AUC-12: 146 ug/mL (146 (41-255)
LPV IQ (Ctrough): 26 (0.7-438)
STUDY 049: DISPOSITION THROUGH 48 WEEKS
There were no gross differences (667/167 vs 400/300) in antiviral activity:
--overall, 21/36 (58%) achieved HIV RNA <400 copies/ml
--83% demonstrated 1.0 log10 copies/ml decrease from baseline
There was a trend toward better tolerability for 667/167 vs 400/300
--lower drug-related diarrhea (11% vs 24%) and vomiting (0% vs 12%) of at least moderate severity
--lower grade 3/4 triglycerides (>750 mg/dL): 26% vs 65%
The 48-week clinical (safety/efficacy abstract is submitted to XV IAC (Bangkok, July 2004).
STUDY 049: PK/PD ANALYSIS SUMMARY OF RESPONSE VARIABLES
The average HIV RNA change from baseline through 48 weeks:
--mean (SD) average change was –1.39 (1.09) log 10 copies/ml with a range of –3.47 to +0.41 log10 copies/ml
The proportion achieving HIV RNA <400 copies/ml:
--21/33 (54%) achieved HIV RNA <400 copies/ml at least once
--16/33 (48%) achieved HIV RNA <50 copies/ml
STATISTICALLY SIGNIFICANT EFFECTS ON AVERAGE HIV RNA CHANGE FROM BASELINE
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P-value
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Unadjusted (simple linear regression)
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Adjusted (multiple linear regression)
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Variable
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LPV fold wt-IC50
(phenotype)
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0.01
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ns
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No LPV mutations
(LPV score)
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0.02
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ns
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No LPV mutations
(ATU set)
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0.04
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ns
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Active NRTIs
(genotype)
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0.02
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0.04
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Active NRTIs
(phenotype)
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0.04
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ns
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LPV IQ
(Ctrough/IC50)
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0.002
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0.007
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STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH ACHIEVING HIV RNA <400 COPIES/ML
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P-value
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Unadjusted (simple linear regression)
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Adjusted (multiple linear regression)
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Variable
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Baseline HIV RNA
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0.03
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0.03
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LPV fold wt-IC50
(phenotype)
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0.01
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ns
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No LPV mutations
(LPV score)
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0.03
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ns
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Active NRTIs
(genotype)
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0.02
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0.04
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LPV IQ
(Ctrough/IC50)
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0.01
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0.03
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UNIVARIATE (Unadjusted) EFFECT OF LPV IQ ON PROBABILITY OF ACHIEVING HIV RNA <400 COPIES/ML
Observed results by quartiles:
Lopinavir Inhibitory Quotient
<5 (n=8): 25% with HIV RNA <400 copies/ml
5-25 (n=8): 53% with HIV RNA <400 copies/ml
25-140 (n=8): 75% with HIV RNA <400 copies/ml
>140 (n=9): 89% with HIV RNA <400 copies/ml
MULTIVARIATE (Adjusted) EFFECTS ASSOCIATED WITH PROBABILITY OF ACHIEVING HIV RNA <400 COPIES/ML
In a multiple regression analysis, higher LPV inhibitory quotient (p = 0.007) and more active NRTI (p = 0.04) were associated with improved virologic response. Similarly, a higher LPV inhibitory quotient (p = 0.026) and lower baseline HIV RNA (p = 0.027) were associated with a higher probability of achieving an HIV RNA <400 copies/mL in a multiple logistic regression analysis. A higher number of active NRTIs was marginally significantly associated (p = 0.052) with achieving an HIV RNA <400 copies/mL.
The authors concluded:
In two separate multiple regression analyses, LPV IQ Ctrough was a significant predictor of antiviral response in these multiple PI and NNRTI experienced patients.
The number of active NRTIs was also a significant predictor of antiviral response in both analyses.
Higher doses of LPV/r may provide LPV concentrations sufficient to overcome certain degrees of reduced LPV phenotypic susceptibility, resulting in a significant treatment effect.
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