Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study

Abstract

The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on C, AUC, and AUC for tenofovir and lamivudine and on C and AUC for efavirenz were within the acceptance criteria (80-125%). For tenofovir disoproxil fumarate, the T, K, and t values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the T, K, and t values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the T values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators' formulations, and both treatments were well tolerated.

Fixed dose drug combinations – are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries

“…• Fixed dose combinations (FDCs) are welcomed across countries illustrated by endorsement from the World Health Organisation • However there are concerns including their rationality, potential to increase adverse drug reactions, dosing schedules with peak effectiveness at different times, lack of titration and potentially higher prices • There is a paucity of data among low-and middle-income countries assessing their value and cost-effectiveness in routine clinical care affecting availability and funding • Perceived benefits regarding FDCs among senior-level personnel working in LMICs include simplifying the treatment scheduleespecially important in complex disease areas, improved adherence rates and tolerability, reduced overall costs and reduced chances of stockouts • Additional perceived concerns include the potential for overtreatment if physicians and patients are not fully aware of their constituents, potential to increase polypharmacy and missed doses have a greater impact on subsequent patient care • Initiatives to enhance the prescribing and dispensing of FDCs where valued include physician and patient education, developing quality indicators around their use, accelerating their registration and companies having realistic pricing expectations • Possible initiatives to reduce or negate the availability of FDCs where there are concerns include a requirement for companies seeking registration to provide robust health technology assessment data to support the application as well as improved physician education and greater interaction with national patient organisations However, some of the perceived difficulties and concerns with FDCs can potentially be addressed through having multiple formulations available for titration purposes, starting FDCs only when deemed safe to do so, and/or addressing pharmacogenetic and pharmacokinetic concerns during FDC development [5,6,20,21]. Alongside this, look to re-formulate large FDCs with dissolving and other formulations [13,22].…”