Date Published: July 5, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Kelly E. Dooley, Peter S. Kim, Sharon D. Williams, Richard Hafner.
An unprecedented number of investigational drugs are in the development pipeline for the treatment of tuberculosis. Among patients with tuberculosis, co-infection with HIV is common, and concurrent treatment of tuberculosis and HIV is now the standard of care. To ensure that combinations of anti-tuberculosis drugs and antiretrovirals are safe and are tested at doses most likely to be effective, selected pharmacokinetic studies based on knowledge of their metabolic pathways and their capacity to induce or inhibit metabolizing enzymes of companion drugs must be conducted. Drug interaction studies should be followed up by evaluations in larger populations to evaluate safety and pharmacodynamics more fully. Involving patients with HIV in trials of TB drugs early in development enhances the knowledge gained from the trials and will ensure that promising new tuberculosis treatments are available to patients with HIV as early as possible. In this review, we summarize current and planned pharmacokinetic and drug interaction studies involving investigational and licensed tuberculosis drugs and antiretrovirals and suggest priorities for tuberculosis-HIV pharmacokinetic, pharmacodynamic, and drug-drug interaction studies for the future. Priority studies for children and pregnant women with HIV and tuberculosis co-infection are briefly discussed.
The spread of HIV has fueled the tuberculosis (TB) epidemic, and in less-developed countries, TB is the most common cause of death in HIV-infected individuals, accounting for 22% (350,000) of HIV-related deaths globally . In 2010, 1.1 million of the 8.8 million incident cases of TB worldwide were among people living with HIV . For patients with HIV and TB, there is now strong evidence that treating both diseases concurrently rather than waiting until TB treatment is complete to start antiretroviral (ARV) drugs decreases mortality [3–6]. For this reason, cotreatment is now the standard of care for most patients. Treatment of drug-sensitive TB still requires 6 months of multidrug therapy, but strategies to shorten the treatment duration are being explored and must be tested among patients with and without HIV infection. The coepidemics of TB and HIV have also fostered the global emergence of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB. As such, there is an urgent need for new TB drugs and drug combinations as well as improved approaches to the treatment of TB, particularly in the context of HIV infection. While the current pipeline of new drugs for TB is more robust than it has ever been, advanced planning and active fostering of pharmacokinetic (PK) and pharmacokinetic interaction (PKI) studies with other antimicrobials and ARV drugs are critical to accelerating development and access of new drugs for populations affected by HIV coinfection. These studies are needed to explore the pharmacologic compatibility and tolerability of future combination drug regimens for HIV-TB-coinfected populations. While some PKI studies can be conducted initially among healthy HIV-seronegative volunteers, especially when metabolic drug interactions are expected to result in the need for dose adjustments, it is essential that follow-up studies be conducted among patients with HIV and/or TB so that variability in PK and pharmacokinetic/pharmacodynamic (PK/PD) relationships can be fully explored.
The current pipeline of new TB drugs represents the most robust portfolio of new drugs in development in the history of TB research. Many of these drugs have advanced to Phase 2 studies and offer the potential for increasingly efficacious TB regimens for both drug-sensitive and drug-resistant disease. Though they represent the future of TB treatment strategies, some of them have or are expected to have clinically significant interactions with current TB drugs and HIV treatment regimens. Thoughtfully selected, appropriately timed PKI studies are essential to ensure that these new regimens will benefit HIV-infected populations as well as those uninfected with HIV.
Though the large burden of TB among pediatric populations is widely recognized, children represent a historically understudied population in TB research. Given that efficacy trials in adult TB patients depend on production and culture of sputum samples during treatment and young children cannot produce sputum samples for testing, dosing recommendations for TB drugs for children are generally based on PK studies rather than efficacy trials. New compounds that have demonstrated efficacy for which a dose has been selected in adults should immediately be tested in children, beginning in adolescents, and then proceeding to progressively younger groups of children. The importance of this is illustrated by the example of INH and RMP. When given to children at the same mg/kg dose as adults, concentrations are much lower, and children were treated with suboptimal doses of these drugs for decades. Only recently were the doses recommended by the World Health Organization increased to reflect these age-related differences in drug disposition . A pediatric dose finding study of bedaquiline among children with MDR-TB is under development by the NIAID-funded International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) network with support from Janssen. Similar dose finding studies are required for all of the new TB drugs in the pipeline as well as many currently existing TB drugs. Development of formulations that can be used in young children is a high priority for all promising investigational TB drugs.
The coepidemics of TB and HIV represent a deadly marriage of global significance. Advances in the treatment of drug-sensitive and drug-resistant TB, though, are likely in the near future given the increased number of drugs in the development pipeline and promising results in preclinical and early clinical studies of regimens involving existing and investigational drugs. To ensure that patients with HIV can fully benefit from new and currently available TB regimens, studies evaluating the safety, pharmacokinetics, and efficacy of coadministered antiretrovirals and antituberculosis drugs must be undertaken, particularly when metabolic drug interactions or overlapping toxicities are likely (Table 1). Consideration and advanced planning of the most pertinent studies should begin early in the course of drug development with guidance from preclinical studies and should be done before phase IIb trials of multidrug TB regimens. While Phase I studies using crossover designs may be employed for drugs with shorter half lives, for drugs with longer half lives or time-dependent kinetics, nesting PKI studies in Phase IIa treatment trials will be the most informative strategy. For drugs whose concentrations are highly dependent on environmental and host factors, including, genetics, PKI studies must be conducted in the relevant populations, including in high-burden settings, rather than extrapolating results from trials conducted among a small subset of participants, such as, healthy volunteers. Advocacy together with funding support from industry, government, and public-private sources will be needed to ensure that PKI involving investigational TB drugs and relevant ARVs is conducted, particularly when interactions are predicted and dose adjustment strategies must be explored. PK studies to find the age-appropriate dose of investigational agents for children should be conducted as soon as a dose going forward in adults is determined, with special attention to drug formulation. Finally, sparse PK sampling in all large clinical trials of new TB drugs or regimens will help define the PK/PD parameters that correlate best with treatment response and determine PK targets to ensure optimized dosing. Concurrent treatment of HIV and TB saves lives, and careful assessment of the pharmacology of coadministered antiretrovirals and antituberculosis drugs will help ensure that new or improved TB regimens will benefit those patients who need them most.