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Instability of lopinavir/ritonavir capsules at ambient temperatures in sub-Saharan Africa: relevance to WHO antiretroviral guidelines
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AIDS: Volume 19(11) 22 July 2005 p 1233-1234
Pau, Alice Ka; Moodley, Neelambal Kb; Holland, Diane Tc; Fomundam, Henrye; Matchaba, Gugu Uf; Capparelli, Edmund Vc,d
aNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
bSouth African Military Health System, Pretoria, Republic of South Africa
cSchool of Medicine
dSchool of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA
eMEDUNSA National School of Public Health, Pretoria, Republic of South Africa
fProject PHIDISA, Pretoria, Republic of South Africa.
Abstract
WHO recommends lopinavir/ritonavir as an antiretroviral option in resource-limited countries. Lopinavir/ritonavir is recommended to be stored at 2-8C until dispensing, and afterwards, may be kept at ≦ 25C for ≦ 2 months. Anticipating lopinavir/ritonavir use in countries lacking adequate cold-chains, we assessed its physical and chemical stability at 35 and 45C. Although maintaining chemical stability for 4 weeks at 35C, at 45C the capsules clumped after 7 days, supporting a need for more temperature-stable formulations for hotter climates.
Lopinavir/ritonavir (co-formulated as Kaletra soft-gel capsule) is among the antiretroviral options recommended by the World Health Organization (WHO) for resource-limited countries [1]. The package labeling recommends that lopinavir/ritonavir capsules should be stored at 2-8C before dispensing, and their potency can be retained at 25C or less for up to 2 months [2]. In sub-Saharan Africa, ambient temperatures often exceed 35-45C. Cold storage is not always available in warehouses, during transport, in pharmacies, or in patients' homes. If significant drug degradation occurs at high temperatures or if the integrity of the capsule formulation is jeopardized, the potential utility and antiviral efficacy of lopinavir/ritonavir may be compromised. The objective of this study was to examine the physical and chemical stability of lopinavir/ritonavir capsules when stored at 35 and 45C for up to 2 months.
Commercially supplied lopinavir/ritonavir capsules kept in high-density polyethylene bottles were placed in incubators maintained at 35 and 45C with high (88-92%) humidity. Six capsules were visually inspected, weighed, and assayed on days 1, 2, and 7, and weeks 2, 4, and 8. For assay, each capsule was dissolved in 10 ml of 1.0% acetic acid and then diluted 1: 1000 in high performance liquid chromatography mobile phase (10 mM potassium dihydrogen phosphate, pH 3.1) 50% volume/volume with acetonitrile in two steps (1: 100 and 1: 10). Lopinavir and ritonavir concentrations were determined by a high performance liquid chromatography method validated for plasma assay with lower limits of quantitation of approximately 90 ng/ml for both drugs. The within and between assay precision were 4.58% coefficient of variation (CV; ± 4.56) and 5.15% CV (± 4.38) for ritonavir and 4.88% CV (± 4.0) and 6.48% CV (± 4.9) for lopinavir. Capsules stored at 4C were assayed concurrently with those stored at 35 and 45C. Stability was expressed as the percentage ratio of the peak area from capsules stored at 35 and 45C to those stored at 4C. The estimated recovery of the dissolution process for lopinavir/ritonavir capsules stored at 4C was 97.2% for lopinavir (± 2.85 SD, CV 10.9%, n = 16) and 103.7% for ritonavir (± 1.03 SD, CV 14.2%, n = 17). Clumping occurred rapidly in the capsules stored at 45C, requiring modification of storage of capsules in individual polypropylene tubes.
At 35C, the gross physical structure of the Kaletra capsules was maintained up to 4 weeks, although the capsules were softened compared with controls. By week 8, the capsules were soft and misshapened, but remained intact (Fig. 1). The mean weight of the capsules increased 10.9% from 1.316 g on day 1 to 1.460 g at week 8, most likely as a result of the absorption of moisture from the environment. At 45C, within 2 days, the capsules were softened, misshapened, and became sticky. By day 7, the capsules were clumped together and became impossible to separate without breaking or loss of the drug-containing liquid matrix.
At 35C, both lopinavir and ritonavir maintained their stability at greater than 95% for up to 4 weeks (99%, CV 2% and 97%, CV 2% for lopinavir and ritonavir, respectively). However, at week 8, only 84% of lopinavir (CV 21.4%) and 90% of ritonavir (CV 18.7%) were recovered compared with the 4C controls. At 45C, as a result of the physical conditions, it was not possible to assay the capsules at weeks 4 and 8 as planned. Only two capsules were available for analysis at weeks 3 and 6. Lopinavir and ritonavir were 101 and 93% of control capsules, respectively, at week 3. At week 6, only 77% of lopinavir and 67% of ritonavir were recovered.
The manufacturer suggested that Kaletra capsules are stable for 2 months at up to 25C. Whereas room temperature is generally 25C or less in most western countries with indoor climate control, the ambient temperatures in the resource-limited countries of sub-Saharan Africa often exceed this level. This pilot study shows that Kaletra capsules maintain their chemical stability for up to 4 weeks, but not 8 weeks, at 35C. Therefore, in patients without home refrigeration or adequate temperature control, during periods of hot weather, no more than a one-month supply can be stored without compromising drug potency. At 45C (a temperature often reached during summer months in some countries), the outer coating of the capsules fused together within a week, making it impossible to separate the capsules without breakage, and rendering the drug supply unusable from a safety standpoint.
In order to provide drugs for worldwide usage, manufacturers should be encouraged to develop formulations that may be stable under storage conditions common in countries where the drugs may be prescribed. Unfortunately, financial incentives to develop temperature-stable formulations to be used in resource-limited areas where such formulations might be most in demand are usually lacking. We undertook this pilot study to provide some initial guidance for lopinavir/ritonavir use in a clinical trial in South Africa, where over half of the study participants reported no access to home refrigeration. Although we attempted to simulate known extremes of temperature and humidity commonly encountered in the summer months in South Africa, a potential limitation of this experiment is that these conditions were maintained constant throughout the duration of the observation period, whereas in actual home environments some fluctuations of temperature and humidity would be expected. Whether incorporating a fluctuating temperature or humidity parameter in this experimental system would affect the chemical and physical stability results is unknown. Despite this limitation, to our knowledge this study provides the first reported data on the potency and physical integrity of any antiretroviral drug when stored at higher than recommended temperatures. Of note is the fact that four other antiretroviral formulations in the current WHO list also require cold-chain for storage, which include ritonavir capsules, saquinavir soft-gel capsules, along with didanosine and stavudine oral powder (both require refrigeration after reconstitution). In order for providers in resource-limited countries to make use of the full complement of the WHO antiretroviral armamentarium, and, more importantly, for their patients to reap the maximal benefits from these medications, manufacturers should be encouraged to make every effort to develop and test more temperature-stable drug formulations.
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