Antiretroviral pharmacokinetics in special patient populations

Jennifer J. Kiser, Courtney V. Fletcher, for

Hepatic impairment

There are limited data on the appropriate dosing of antiretroviral drugs in patients with varying degrees of hepatic impairment.

Josep Mallolas presented a study evaluating fosamprenavir dosing and pharmacokinetics in HIV-infected subjects with mild and moderate hepatic impairment. [15]

Thirteen subjects with mild hepatic impairment (Child Pugh score 5-6) received fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily (Group A). Ten subjects with moderate hepatic impairment (Child Pugh score 7-9) received fosamprenavir 300 mg twice daily (as the oral suspension) plus 100 mg of ritonavir once daily (Group B). Eight subjects with moderate hepatic impairment received fosamprenavir/ritonavir 700/100 mg once daily (Group C). Ten patients with normal hepatic function received fosamprenavir/ritonavir 700/100 mg twice daily (Group D/controls). All subjects underwent intensive pharmacokinetic studies (including measurement of unbound amprenavir concentrations at two time points) two weeks after initiating fosamprenavir/ritonavir.

Patients in Group A had total amprenavir plasma AUCs 22% higher and Cmins that were similar to controls, but amprenavir unbound Cmin was 2-fold higher in patients in Group A vs. controls. Subjects in Group B had amprenavir AUC and Cmin 27% and 57% lower, respectively than controls, but the amprenavir unbound Cmin was similar for subjects in Groups B and D. Subjects in Group C had amprenavir AUC and Cmin 24% and 65% lower than controls, and unbound amprenavir Cmin that were 40% lower on average than controls.

The investigators concluded that the reduced ritonavir dose regimen of fosamprenavir 700 mg twice-daily plus ritonavir 100 mg once daily, is the appropriate dose for subjects with mild hepatic impairment. However, neither dosing strategy appeared adequate for subjects with moderate hepatic impairment. Thus, they speculate that fosamprenavir 450 mg twice daily plus ritonavir 100mg once daily would provide adequate exposures for patients with moderate hepatic impairment, though there are no pharmacokinetic or safety data with this dosing strategy.

The pharmacokinetics of maraviroc following a single 300 mg dose in subjects with mild and moderate hepatic impairment were compared to the pharmacokinetics in subjects with no hepatic impairment. [16]

Maraviroc AUC and Cmax were increased 25% and 11%, respectively in subjects with mild hepatic impairment relative to those with no hepatic impairment. Maraviroc AUC and Cmax were increased 46% and 32%, respectively in subjects with moderate hepatic impairment relative to those without hepatic impairment.

Further studies are necessary to determine if dose adjustments may be necessary for subjects with moderate hepatic impairment.

Renal impairment

Sangeeta Agarwala presented a study evaluating the pharmacokinetics of unboosted atazanavir in persons with severe renal impairment including those on hemodialysis. [17]

This was an open-label, parallel design study with 3 groups (controls, severe renal impairment not on hemodialysis, and hemodialysis) of HIV negative subjects (n=10 per group). Subjects with severe renal impairment not receiving dialysis had atazanavir AUCs 19% higher than age, weight, and gender matched controls with normal renal function.

Subjects on hemodialysis had atazanavir AUCs 42% lower on dialysis days and 28% lower on non-dialysis days compared to controls. Though the mechanism for the reduction in atazanavir exposures in those on hemodialysis is not known, the investigators speculate that there may be decreased gastric acid production in hemodialysis patients.

These investigators (from Bristol Myers Squibb) commented that for patients receiving hemodialysis clinicians could consider using atazanavir/ritonavir to compensate for the reduction observed in this study in atazanavir concentrations. While the basis for this recommendation is understandable it is important to stress that no pharmacokinetic or safety data are available at this time to support this recommendation.


Efavirenz pharmacokinetics in children

David Burger described the pharmacokinetics, efficacy, and tolerability of efavirenz tablets and capsules when used in children ages 2-16 years and dosed per the weight-based manufacturer’s guidelines. [18]

307 efavirenz plasma concentrations were obtained in 33 children. 8.8% of samples were less than 1000 ng/mL, while 14.7% of samples were greater than 4000 ng/mL. There was a trend towards a higher proportion of samples greater than 4000 ng/mL in the children who reported central nervous system adverse effects vs. those without these effects (p=0.23, 26 vs. 13%).

All 27 children who remained on efavirenz achieved viral loads of less than 50 copies/mL, despite the occasional presence of subtherapeutic concentrations in 12 of these children most likely due to sporadic non-adherence.

These data suggest that efavirenz tablets and capsules are effective in children who are able to tolerate the drug and provide some validation of the dosing guidelines for children contained in the manufacturer’s dosing guidelines.

This study raises the question as to whether those children who had CNS adverse events and were found to also have efavirenz concentrations greater than 4000 ng/mL might have benefited from therapeutic drug monitoring and dose adjustment.

Ritonavir-boosted saquinavir formulations

The United States Food and Drug Administration requested that Roche evaluate the pharmacokinetics of ritonavir-boosted saquinavir following opening the Invirase capsules and dissolving them in various vehicles in an attempt to find an acceptable means of administering the drug to children 4 months to 5 years of age.

Diane McKay presented an open-label, randomized, four period, crossover relative bioavailability study of this strategy in 27 healthy adult volunteers. [19]

Volunteers received ritonavir 100 mg as the oral solution plus Invirase® capsules either unopened (A), opened or suspended in simple syrup (B), baby formula (C), or jelly jam (D). The bioavailability of saquinavir was 10, 60 and 40% higher in simple syrup, baby formula, and jelly jam, respectively, relative to the unopened capsules. The next step is to evaluate this strategy in children. All three vehicles will be used in the studies with children.

Atazanavir/ritonavir and tenofovir in HIV-infected adolescents and young adults

Children appear to have faster apparent oral clearances of tenofovir and atazanavir than adults. [20, 21] Additionally, there is a bidirectional interaction between these drugs. [22]

Jennifer Kiser presented data evaluating the interaction between atazanavir/ritonavir and tenofovir in HIV-infected adolescents and young adults. [23]

Atazanavir pharmacokinetics appeared similar to values observed in older adults on the combination (Taburet AM, AAC 2004;48(6):2091-6). Though a higher tenofovir AUC may have been expected based on a previous study in healthy volunteers receiving the combination, this was not observed in this study. Apparent oral clearance increased as weight increased for atazanavir, ritonavir, and tenofovir. Estimated creatinine clearance was also associated with tenofovir apparent oral clearance.

The geometric mean for intracellular tenofovir diphosphate concentrations in 22 subjects was 94 fmol/10^6 cells (63% CV) and were similar to that reported by Hawkins in a small number of patients (Hawkins T. JAIDS 2005;39(4):406-11).


  1. Mallolas J et al. Fosamprenavir (FPV)/ritonavir (RTV) dose adjustment for patients with mild and moderate hepatic impairment (HI) (APV10017). Abstract 1.
  2. Abel S et al. An open, parallel group study to compare the pharmacokinetics, safety and toleration of a single oral dose of maraviroc in subjects with mild and moderate hepatic impairment with subjects with normal hepatic function. Abstract 8.
  3. Agarwela S et al. Pharmacokinetics of atazanaivr in severely renally impaired subjects including those on hemodialysis. Abstract 2.
  4. Burger D et al. Pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children in Munich, Germany. Abstract 11.
  5. McKay D et al. Relative bioavailability and palatability of ritonavir-boosted opened Invirase capsules suspended in three food vehicles compared to ritonavir-boosted unopened Invirase capsules. Abstract 6.
  6. Hazra R. AAC 2004;48(1):124-129
  7. Kiser JJ. 12th CROI, 2005. Abstract 767.
  8. Agarwala S. 6th International Workshop on Clinical Pharmacology of HIV Therapy 2005; abstract 16.
  9. Kiser JJ et al. Pharmacokinetics (PK) of antiretroviral regimens containing tenofovir disoproxil fumerate (TDF) and atazanavir/ritonavir (ATZ/r) in adolescents and young adults with HIV infections – Study ATN056. Abstract 12.

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