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Reports From the 7th HIV Pharmacology Workshop

January-March 2006


Effect of Pregnancy on PK of Protease Inhibitors

Previous studies investigating the pharmacokinetics (PK) of protease inhibitors (PIs) show reduced exposure during pregnancy. M. Regazzi and coworkers from a multicenter cohort in Italy evaluated nelfinavir and lopinavir plasma levels in a group of HIV-positive pregnant women after receiving multiple doses.

A group of 29 women in the 3rd trimester of pregnancy were selected from an ongoing national surveillance study. All women achieved steady-state plasma concentrations while on a HAART regimen containing nelfinavir (1250 mg BD, n=20) or lopinavir/r (400/100 mg, BD, n=9).

Nelfinavir samples were obtained pre-dose (Ctrough) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours post-dose. For lopinavir, Ctrough and 3 hour plasma samples were obtained. The results were compared to results from a control group of HIV-positive non-pregnant women (nelfinavir: n=21; lopinavir: n=12).

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Additionally, the investigators evaluated placental transfer in a subgroup of 6/20 mother/infant pairs receiving nelfinavir and 6/9 receiving lopinavir/r by comparing drug concentrations in samples collected at delivery.

They found median nelfinavir PK values were: AUC (0-12h) 25.76 mcg.h/mL (range: 12.61-42.74) in pregnant women vs. 32.49 mcg.h/mL (range: 19.16-63.81) in controls (ptrough was significantly (pMedian lopinavir Ctrough levels were similar in pregnant women and controls: 4.3 mcg/mL (range: 3.0-8.3) and 5.2 mcg/mL (range: 0.3-16.0). Only 1/9 pregnant women had Ctrough level below the recommended lopinavir target of 4.0mcg/mL. The median C3h was significantly lower (pThe investigators concluded that HIV-positive pregnant women receiving nelfinavir without any concomitant PIs frequently show subtherapeutic levels of nelfinavir in late pregnancy. They found that lopinavir showed better PK, with similar Ctrough levels in the two groups.

They wrote, "The difference between the two drugs in achieving therapeutic levels may be explained by the inclusion of ritonavir in lopinavir regimen. Nelfinavir and lopinavir did not cross the placenta to an appreciable extent and thus should not be expected to provide any direct protection for the newborn."


References

  1. Regazzi R, Villani P, Floridia M et al. Effect of pregnancy on protease Inhibitors (PIs) pharmacokinetics in HIV-1 infected women. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 27.

  2. Khuong-Josses M-A, Boussaïri A et al. Nelfinavir plasma concentrations in 40 pregnant women. 13th CROI. Abstract 707.

  3. Stek A, Mirochnick M, Capparelli E et al. Reduced lopinavir exposure during pregnancy: preliminary pharmacokinetic results from PACTG 1026. XV Intl AIDS Conference, Bangkok. Abstract LbOrB08.

  4. Lyons F, Lechelt M, Magaya V et al. Adequate trough lopinavir levels with standard dosing in pregnancy. 13th CROI 2006, Denver. Abstract 709.

  5. Mirochnick M, Stek A, Capparelli E et al. Adequate lopinavir exposure achieved with a higher dose during the third trimester of pregnancy. 13th CROI, Denver. Abstract 710.


Relationship Between Nevirapine Concentrations and Virological Failure in a Clinical Setting

Previous studies have reported high frequency of sub-optimal nevirapine Ctrough levels but no guidelines have suggested a way to manage these patients. Should a clinician confirm the inadequate concentration on another sample because of high intra-patient variability or increase nevirapine dose?

N. Machefert from the Centre Hospitalier Universitaire, Toxicologie et Pharmacocinétique, Poitiers, France, and coworkers performed a retrospective assessment of the risk of virological failure in a clinical setting for patients having one or more sub-optimal nevirapine Ctrough (The authors evaluated 38 patients receiving standard nevirapine dose as part of their antiretroviral regimen. Nevirapine Ctrough concentrations were determined from 245 samples collected at each clinic visit throughout the course of their treatment. Viral load and adherence, recorded at each clinic visit, were also evaluated. Virological failure was defined as >1000 copies/mL. The number of patients with one or more Ctrough <3 ug/mL were compared to the virological failure group.

Patients received nevirapine for a mean of 700 days; 8/38 patients had virological failure. There was an average of 6 Ctrough measurements available per patient. The investigators found 24/38 (63%) patients had at least one inadequate Ctrough during the course of their treatment. 7/8 (88%) patients had more than one inadequate Ctrough in the viral failure group vs. 9/30 patients in the group without virological failure, p=0.01. Additionally 6/8 patients in the virological group were considered as non-adherent (confirmed by undetectable plasma concentration measurement during the course of their treatment).

They reported that the intra-individual variability was significant with a mean value of 35% [range: 5-200%] in all patients but only 20% [range: 5-45%] excluding non-adherent patients. The investigators wrote, "This study confirms the high frequency of inadequate Ctrough in clinical settings and suggests that only patients exhibiting more than one inadequate NVP Ctrough are at risk of virological failure. In routine practice, before nevirapine dosage adjustment, inadequate Ctrough should be confirmed and adherence should be assessed."


Reference

  1. Machefert N, Dupuis A, Le Moal G et al. Relationship between nevirapine concentration and virological failure assessed in a clinical setting. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 70.


Using Enzyme Inducers to Reduce the Half-Life of Nevirapine

Several studies have reported the development of resistance to nevirapine even after taking a single dose of the drug, which is commonly used in the resource-limited setting for the prevention of mother to child transmission. This is likely due to the long half-life of nevirapine that results in the drug being found in blood for many days after taking the one dose.

A poster from Rafaella L'homme and coworkers from the Radboud University Nijmegen Medical Centre presented findings from a study exploring the novel strategy of using enzyme inducers to reduce nevirapine half-life and thereby reduce the risk of developing resistance.

This small study evaluated the use of several different strategies including using carbamazepine, phenobarbital, phenytoin, St. John's Wort tea, retinyl palmitate and beta-carotene, and cholecalciferol.

This was a phase-I single-centre, open-label, 2-period, 9-group, PK study. A single 200 mg dose of nevirapine was administered to 36 HIV-negative non-pregnant women in both period 1 and 2, blood samples were taken twice weekly for 21 days. In period 2 additional interventions (single-dose carbamazepine, phenobarbital or phenytoin; phenytoin for 3 or 7 days; St Johns Wort, vitamin A or cholecalciferol for 14 days) were administered to all participants except for the control group. The primary end point was the ratio of nevirapine half-life in period 2 to nevirapine half-life in period 1.

Three of the interventions resulted in the half-life of nevirapine being significantly reduced. These included a single 400mg dose of carbamazepine (p=0.002), once a day 184mg phenytoin for three days (p=0.001) and once a day 184mg phenytoin for seven days (p=0.002). The half-life of nevirapine was reduced by 35.3%, 38.2% and 35.9% respectively. This resulted in a 4.5-8.8 day reduction in time to when nevirapine could not be detected in blood. The other five interventions had no effect on the nevirapine half-life.

These interventions now need to be studied in the real world setting to determine if this will lead to a decreased risk of developing resistance to nevirapine among pregnant women taking single dose nevirapine to prevent HIV transmission to their newborns.


Reference

  1. L'homme R, Dijkema T, A. van der Ven A et al. Enzyme inducers reduce nevirapine half-life. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 5.

From HIV i-Base.





  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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