Box 3 | Formulations and co-formulations

The approval of Atripla (Bristol–Myers Squibb/Gilead) — a single tablet, once-a-day co-formulation of efavirenz, tenofovir and emtricitabine — in July 2006, signalled the start of a new era in antiretroviral therapy. Co-formulations greatly simplify treatment, and put HIV infection in the same class as hypercholesterolaemia, hypertension or gastroesophageal reflux disease — all chronic conditions that can be controlled with a single pill taken once daily. Similar comments apply to the Triomune co-formulation of generic nevirapine, stavudine and lamivudine, which is now one of the most widely used anti-HIV regimens in the world, albeit a twice-daily regimen.

Atripla may be the new standard for initial treatment. However, co-formulations come with a price. First, regimens containing drugs from more than one manufacturer may require months or years of negotiation just to agree that such a product can be developed. Co-formulations can involve drugs with chemical incompatibilities, and may require different excipients. Such products include only a single fixed dose of each component; this makes dose individualization — for example, in young children or patients with renal insufficiency — difficult or impossible.

New formulations often improve the pharmacokinetic properties and extend the patent life of existing drugs. This strategy has figured prominently in the marketing of drugs for other chronic diseases, as new formulations, often sustained-release formulations, frequently appear when the patent expires on an existing product.

The development and approval of the tablet formulation of the lopinavir/ritonavir co-formulation Kaletra (Abbott) using melt-extrusion technology, is an example of the kind of improvements we can expect in the future. This formulation reduced the pill burden from six capsules to four tablets per day, and improved the temperature stability of the components, allowing room temperature storage rather than refrigeration. As a consequence, lopinavir may now be made available in areas without reliable refrigeration.

Radical modifications in formulation, such as the development of a depot-like, once-a-month, injectable or transdermal antiretroviral, are beyond the reach of current drugs. As potency and pharmacokinetic properties improve, however, such approaches may appear on the treatment horizon.