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Background:  Refrigeration is recommended for didanosine (ddI) and stavudine (d4T) pediatric oral solutions and Kaletra (LPV/RTV) capsules, but data are lacking regarding their stability at non-refrigerated temperatures. These drugs are increasingly prescribed for patients in the developing world, many of whom lack access to refrigeration and live in climates with temperatures that can exceed 40°C. We examined the stability of these 3 drug formulations after storage under experimental conditions for as long as 11 weeks at temperatures up to 55°C.

Methods:  ddI and d4T were reformulated according to manufacturers’ instructions. For each drug, 1-mL aliquots were kept at 4°C, 15°C (d4T only), 25°C, 35°C, 45°C, and 55°C. At each temperature, ddI and d4T stability was tested on day 1, and at 1, 2, 4, and 8 weeks. LPV and RTV were assayed from Kaletra capsules stored at these same temperatures for 11 weeks. At each temperature and time point, 3 aliquots were tested. ddI and d4T were assayed using reversed-phase high-pressure liquid chromatography (HPLC), and Kaletra with mobile-phase HPLC. The 3 results were averaged; the average area of drug peak at 1 temperature and time point is expressed as a percentage difference from the drug peak area of stock solution kept at 4°C for the same time point.

Results:  ddI was stable through week 4 at temperatures as high as 45°C. At week 8, the change in ddI drug peak area compared with the 4°C control was negligible at 35°C or less, but was –16.0% at 45°C and –58.1% at 55°C. d4T was stable at 8 weeks only if stored at 10°C or cooler (d4T drug peak area was –18.9% after 8 weeks at 15°C). At 2 weeks, the d4T drug peak area compared with 4°C control was –16.6% and –83.9% for drug stored at 25°C and 35°C, respectively. After 4 weeks at these temperatures, the d4T drug peak area was –31.3% and –95.8%, respectively (and at 8 weeks, –52.8% and –99.9%). For Kaletra, LPV and RTV loss was negligible for temperatures as high as 35°C at 11 weeks. At 11 weeks, LPV drug peak area was –13.1% at 45°C and –18.2% at 55.0°C, and RTV drug peak area was –42.5% at 45°C and –61.3% at 55°C.

Conclusions:  Pediatric oral solutions of ddI are stable at temperatures as high as 35°C for 8 weeks; d4T solutions, however, show significant loss of stability after 4 weeks at 25°C, and the majority of drug is lost after even 1 week at 35°C. The LPV component of Kaletra is stable at temperatures as high as 45°C for 11 weeks, and the RTV component is stable at temperatures as high as 35°C for 11 weeks.

Keywords: Stability; Didanosine; Stavudine