Pharmacokinetic study of Triomune-40 in Malawi: higher d4T exposure suggests importance of using lower dose formulations of d4T

5 February 2007. Related: Antiretrovirals.

Simon Collins, HIV i-Base

A study from Hosseinipour and colleagues published in the 2 January edition of AIDS reported results from a study in Malawi that could have clinical implications for use of Triomune, the most widely prescribed ARV regimen in resource-limited settings. [1] Triomune is a fixed dose combination of d4T (stavudine), 3TC (lamivudine) and nevirapine.

This small study looked at the pharmacokinetics and bioequivalence of generic and trade formulations of stavudine, lamivudine, and nevirapine in 12 HIV positive Malawian (6 men, 6 women), in a randomised, open label, cross-over study.

Either generic or tradename drugs were used for 21 days, and then patients were switched to the alternative formulation.

At the end of each period, six blood samples were collected over 8 h. Bioequivalence was achieved if the 90% confidence interval (CI) for the geometric mean ratio (GMR) of generic trade formulations for maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) was within 0.8-1.25.

Baseline characteristics included a mean age 38 years (SD±7.7), mean weight 71.2 kg (SD±7.0), mean height 164.8 cm (SD±6.25), and mean body mass index 26.2 kg/m2 (SD±3.6). There were no significant differences in these parameters according to randomisation arm. Subjects had been taking Triomune-40 for a mean of 11.4 months (SD±0.9; range, 10-12). Five subjects were taking amitriptyline for pain control of grade 1 neuropathy. Nine (75%) reported grade 1 neuropathy at the time of study entry.

Similar exposures were obtained between generic and trade formulations for 3TC and NVP, with the GMR 90% CI for all pharmacokinetic parameters evaluated. However, the Cmax (GMR 90% CI, 1.2-1.7) of generic d4T was markedly higher than the trade formulation. The GMR for stavudine, lamivudine, and nevirapine were 1.4 (90% CI, 1.2-1.7), 1.1 (90% CI, 0.8-1.6), and 0.9 (90% CI, 0.7-1.2), respectively, for Cmax; and 1.1 (90% CI, 1.0 1.2), 1.0 (90% CI, 0.7-1.3), and 0.9 (90% CI, 0.7-1.1), respectively, for AUC 0-8hr. Regardless of formulation, these patients had higher nevirapine exposures compared with historical reports of Western HIV-positive patients.

Qualitative data based on interviews revealed that three of the nine subjects who reporting grade 1 neuropathy on the generic formulation believed their symptoms decreased while on the trade formulation. Although d4T Cmax and AUC values were significantly higher with the generic formulation than with the trade formulation in all subjects (p<0.006), there were no differences in Cmax (p=0.32) and AUC (p=0.46) in the three subjects reporting fewer symptoms. Also, there were no differences in the change in d4T exposure in the three subjects reporting less neuropathy while on the trade formulation compared with the six subjects not reporting a change (p=0.43).

In the discussion of the article, the investigators highlighted that this study showed that performing PK studies was feasible and important. The suggested that since d4T is primarily absorbed in the proximal intestine, the generic formulation may have dissolved faster, leading to increased drug absorption, but they also acknowledge that the small number of patients, and limited sample (3 samples over 8 hours) limit these conclusions and that further investigation is warranted.

The study also showed increased exposure to nevirapine regardless of formulation, which could not be explained by body weight, which at 60-80 kg was comparable to a Western population. This may be explained by an increased frequency of a cytochrome P450 2B6 polymorphism, which has been linked to lower rates of metabolic activity and higher nevirapine exposures, including in a Ugandan cohort. This same variant allele has been identified in a Ugandan cohort and was also associated with higher nevirapine concentrations. Studies are currently underway to evaluate this.

Comment

Of three components of Triomune, higher exposure to d4T is most associated with serious side effects, and an incidence of neuropathy in 20% of patients has been reported in d4T-based roll out programmes. Many patients in the poorest programmes cannot switch to alternative options, associated for example with a switch to AZT, where a years treatment with d4T/3TC/NPV costs US $121 and AZT/3TC/NVP costs US $210.

This PK study adds to the growing number of reports suggesting that using a lower dose of d4T reduces toxicity without risking viral rebound. [2, 3]

However, where d4T-based treatments continue to be widely used, switching to Triomune-30 (which uses 30mg dose of d4T), especially after a period of initial treatment, may be an important management option, when alternative RTIs are either unavailable or contraindicated.

The relationship between d4T exposure and symptoms would not be expected to be seen in such a short trial. Neuropathy is a slowly progressive disease and symptoms frequently continue for up to 2 months after discontinuing d4T before any improvement is expected.

References:

1. Hosseinipour MC, Corbett AH, Kanyama C et al. Pharmacokinetic comparison of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian adults. AIDS: Volume 21(1) 2 January 2007 p 59-64.
2. Lowering dose of d4T can maintain efficacy and reduce side effects. HIV Treatment Bulletin Volume 5 Number 7 Aug/Sep 2004.
   http://www.i-base.info/htb/2776
3. Lower doses of d4T produce similar efficacy and reduced side effects. HIV Treatment Bulletin Volume 4 Number 10 December 2003.
   http://www.i-base.info/htb/2789