New PK data for protease inhibitors

Polly Clayden, HIV I-Base

Three posters from the PACTG provided PK data that will help guide dosing of atazanavir (ATZ), with or without ritonavir (RTV), across different age groups and in children with different levels of treatment experience; with lopinavir/ritonavir (LPV/r) in infants <6 months and in combination with saquinavir (SQV) or an NNRTI in PI-experienced children and adolescents.

Atazanavir with or without ritonavir in infants, children and adolescents

Richard Rutstein and coworkers presented findings from PACTG 1020A – a phase I/II study of ATZ and RTV to determine safety, PK and dose of ATZ powder and capsules in naive and experienced HIV-positive children age 91 days to 21 years with baseline viral load >5,000 copies/mL from the United States and South Africa. [1]

In this study the population AUC target was set at 45,000 ng*h/mL. There were 8 groups based on age/formulation; groups 1 to 4, received ATZ alone and groups 5 to 8, received boosted ATZ.

The starting dose of ATZ was 310mg/m2 daily, which was adjusted based on 24 hour PK and safety data on day 7 in the first 5 patients in each group. Acceptance criteria included: no patient with AUC <15,000ng*h/mL; at least 4/5 patients in cohort with AUC >30,000ng*h/mL and at least 4/5 patients in cohort with Cmin >60ng*h/mL. Safety criteria included:  no life-threatening toxicities, </=1 grade 3 or 4 toxicity (not including bilirubin), </=2 patients with total bilirubin values >5.1xULN. If PK and safety criteria were met, an additional five patients were enrolled at that dose. If criteria were not met, a new cohort of five new patients would be started at a higher (or lower) starting dose: 205, 310, 415, 520, 620 mg/m2.

181 patients have been enrolled (66% from the United States) of whom 107 remain on study; 6 dosing cohorts remain open with doses that passed PK and safety criteria:

  • Group 3: 2 to 13 years on ATV capsules
  • Group 4: >13 years on ATV capsules
  • Group 5: <2 years on ATV powder/RTV boosted
  • Group 6: 2-13 years on ATV powder/RTV boosted
  • Group 7: 2-13 years on ATV capsules/RTV-boosted
  • Group 8:>13 years on ATV capsules/RTV boosted.

PK, virological response at 24 weeks, and selected safety (bilirubin and electrocardiogram abnormalities) data on the first 10 patients in each cohort are shown in the table (medians and frequencies).

Table 1: Results from PACTG 1020A

Group 3c 4c 5p/r 6p/r 7c/r 8c/r
Median age 10.2 15.0 1.2 4.8 9.7 17.0
Median dose mg/m2 551.0 600.0 321.0 306.5 212.0 194.5
Median dose mg 600 900 150 200 250 375
Median AUC µg*hr/mL 42.3 67.1 33.8 51.2 43.7 41.9
Median Cmax µg/mL 7.2 7.0 7.4 4.5 4.9 3.9
Median C24hr ng/mL 317.6 676.4 373.0 1045.2 634.0 887.5
Median log change VL -1.23* -0.58 -2.40* -1.88* -1.10* -1.48
# =400 copies/mL week 24 5/9 1/6 7/8 8/10 5/8 3/5
# Total bilirubin >5.1 ULN 1 2 0 0 2 3
# Abm PR 6 2 1 1 2 1

c=capsules, p=powder, r=RTV boosted

Both groups 1, 91days to </=2 years and 2, >2 years to 13 years failed PK criteria at both 310 and 620 mg/m2 doses after which, ATZ powder was only used with RTV boosting.

The investigators reported that 74/181 patients discontinued for the following reasons: 20 toxicity; 14 virologic failure; 15 lost to follow-up or the site closing; 17 non-adherence or intolerance; 1 death (pneumonia) and 7 other.

In their conclusions, the investigators reported considerable variability between patients in children receiving ATZ alone, but this was variability was less when boosted with RTV. Like other PIs, ATZ appears to require higher doses on a mg/m2 basis in children as compared to adults particularly when unboosted. The use of ATZ powder without RTV was not recommended. The use of ATV capsules without RTV boosting required high doses. They noted that the Cmax levels were high (7006 ng/mL with 620mg/m2 dose; 500-600mg/m2 required to meet target) so may be associated with toxicity risk.

They also found ATZ with or without RTV resulted in viral load <400 copies/mL at 24 weeks in 41/52 (79%) of naive patients and 23/54 (43%) of PI experienced (but with phenotypic susceptibility to ATZ: IC50 fold change <10) patients (by intent-to-treat analysis).

They reported that the final accepted dose was 310mg/m2 for group 5 (91 days to </= 2 years old) and group 6 (>2 years to </=13 years old), using ATZ powder, with or without RTV. For group 7. (>2 years to </=13 years old) and group 8 (>13 years to </=21 years old) the final accepted dose was 205mg/m2.

Lopinavir/ritonavir in infants <6 weeks of age

LPV/r has been suggested as primary therapy for very young babies, but to-date there are no PK and efficacy data for infants <6 weeks of age.

Jorge Pinto and coworkers presented results from PACTG P103, a prospective, phase I/II, dose-finding trial that evaluated LPV/r at a dose of 300/75 mg/m2 twice daily plus two NRTI in infants >/=14 days and <6 weeks old. [2]

The infants (n=8) had a 12-hour PK evaluation performed after 2 weeks of treatment with LPV/r; LPV and RTV concentrations were measured by HPLC. Doses were increased by 50% to maintain LPV pre-dose (Cpre) >1mcg/mL and AUC <170 mcg*hr/mL. Infants who did not reach target after dose adjustment discontinued treatment.

In this study a virologic endpoint was reached if viral load was >400 copies/mL at 16 weeks or >4000 copies/mL after 16 weeks. All evaluations were on an intent-to-treat analysis.

The median age of the infants at enrollment was 5.6 (range: 3.6 to 5.9) weeks and all completed >/=24 weeks of follow up. Their median baseline viral load was 5.9 (range 4.7 to 6.5) log10 copies/mL and CD4% was 45% (range 29 to 59%).

7/8 infants completed the PK evaluation at a median age of 7.2 (range 5.5 to 8.0) weeks at a LPV dose of 279 (range 246 to 305) mg/m2 q12h. The median parameters were: AUC, 33.0 (range 27.9 to 62.0) mcg*hr/mL; Cpre, 2.6 (range 1.1 – 4.9) mcg/mL; Cmax, 3.8 (range 2.8 to 7.2) mcg/mL and CL/F (L/hr/m2), 9.4 (range 3.2 to 12.8).

The investigators reported no grade 3 or higher adverse events related to study treatment, but 2/8 infants (25%) had grade 3 neutropenia at week 8, (considered possibly related to NRTIs). No child reached a virological endpoint at week 16 but 1/8 (12%) reached a virological endpoint at week 24 because of non-adherence.

There were no significant changes in CD4 percentage from baseline to week 24 in 4/4 infants with data available.

In conclusion, the investigators noted that LPV/r-based HAART at a dose of 300/75 mg/m2 BID was well tolerated. As expected, the LPV AUC (med AUC, 33 mcg*hr/mL) in this age group was significantly lower than seen previously in older cohorts ages 6 weeks to 6 months (med AUC, 67.5 mcg*hr/mL) and 6 months to12 years (med AUC, 76.9 mcg*hr/mL).

They found great interpatient variability with LPV pre-dose concentrations, but median values were stable over time.They noted that virological response did not correlate with week-2 PK results and that despite the lower LPV exposure, by 24 weeks, 7/8 infants (87%) had viral load <400 copies/mL.

They wrote: “Longer follow-up will help elucidate the impact of the lower LPV exposure on virologic efficacy in very young infants.”

High dose lopinavir with saquinavir

Brian Robbins and coworkers reported findings from PACTG P1038, an open-label, phase I/II study of high-dose LPV/r in children and adolescents ages 2 to 18 failing >6 months of PI therapy with viral loads >5000 copies/mL and LPV fold-change resistance >/=5 by phenotype resistance testing. [3]

Patients received LPV/r 400/100 mg/m2 every 12 hours (group 1, no concurrent non-nucleoside reverse transcriptase inhibitor (NNRTI), maximum LPV dose 667 mg) or 480/120 mg/m2 every 12 hours (group 2, with concurrent NNRTI, maximum LPV dose 800 mg).

Intensive 12-hour PK sampling was conducted at 2 weeks and SQV 750 mg/m2 every 12 hours (maximum dose 1600 mg) was added if the week 2 LPV inhibitory quotient (IQ) was <15. SQV PK was determined at week 6.

26 patients were enrolled in this study of which 19 completed initial PK studies. The median age of the 19 evaluable patients was 14.2 years (range 7.7 to 17.6), 16 were in group 1, and 3 in group 2. All patient evaluated except for 1 required the addition of SQV, based on week 2 LPV IQ.

Of the 20 patients scheduled for SQV, 4 were non-adherent (2 could not take the pills). The high doses of LPV/r, with or without SQV, were well tolerated in this group.

Only 1 patient withdrew because of hypersensitivity and none because of drug toxicity. No increase in QTc was associated with these drug exposures. The median inhibitory quotient was 1.3 with a range of 0.2 to 29.8. The median (range) pharmacokinetic parameters are shown in the table below.

In this evaluation LPV exposure showed high inter-patient variability, not correlated with age or gender. Addition of SQV did not alter LPV pharmacokinetics.

The investigators concluded, “A combination of high-dose LPV/r with SQV can be safely used in children and adolescents with HIV infection”.

Table 2: PK parameters of high dose lopinavir with saquinavir

PK parameters LPV PK Group 1 (n=16) LPV PK Group 2 (n=3) LPV PK Overall (n=19) SQV PK Overall (n=16)
AUC (µg*h/mL 155.4 (62.8-305.5) 162.2 (63.8-185.7) 157.2 (62.8-305.5) 33.7 (4.4-76.5)
Cmax (µg/mL 16.8 (6.7-29.8) 15.8 (8.28-7.2) 17.2 (6.7-29.8) 3.6 (0.6-8.3)
C0 and C12 average (trough) (µg/mL) 10.5 (4.1-25.3) 10.8 (5.58-14.8) 10.8 (4.1-25.3) 2.1 90.2-4.1)
Cl 9l/h/m2 2.53 (1.29-6.32) 3.01 (2.53-7.39) 2.58 (1.29-7.39) 23.1 (8.9-184.5)


All references are to the Programme and Abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles.

  1. Rutstein R, Samson P, Kiser J, et al. The PACTG 1020A protocol: Atazanavir with or without ritonavir in HIV-infected Infants, children, and adolescents. Abstract 715.
  2. Pinto J, Robbins B, Chen J, et al. Pharmacokinetics and 24-Week efficacy and safety of lopinavir/ritonavir in HIV-1-infected infants <6 weeks of age. Abstract 716.
  3. Robbins B, Havens P, Capparelli E, et al. Pharmacokinetics of high-dose lopinavir/ritonavir with and without saquinavir or NNRTI in HIV-infected paediatric and adolescent previously treated with PI. Abstract 717.

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