Commentary by Tom Polasek, MD, PhD, Director of Clinical Pharmacology, Certara
The high morbidity and mortality rates of COVID-19 infection in the elderly highlight the importance of clinical pharmacology factors in this “special population” that influence clinical outcomes and drug development success. The aim of this short article is to initiate a discussion about drug development in the elderly relevant for COVID-19.
Pharmacotherapy in older patients is rarely easy; it is complicated by changes in pharmacokinetics that may result in toxic drug exposures, increased pharmacodynamic sensitivities, and less physiological “reserve” to deal with the adverse consequences of drug treatment. Older patients are generally sicker than younger patients. They have more co-morbidities and take more drugs, meaning additional drug-drug interactions. These factors put elderly patients at greatly increased risk for adverse drug reactions (ADRs) compared with their younger counterparts.
Dedicated clinical studies are sometimes required in the elderly to address these issues i.e., to answer specific questions on efficacy and/or safety, perhaps with a different dose regimen than previously studied. Sometimes, sub-analyses of the larger studies are sufficient. Sponsor generated product information (PI) or independent drug monographs then provide guidance to prescribers on dosing, in particular, in those older patients with significant renal and hepatic impairment. Otherwise, prescribers find themselves in a prescribing “black hole”. The “start low and go slow” strategy is used with regular clinical assessment and empiric dose adjustments as required. This works for chronic diseases. However, the mantra fails for acute presentations, including most infectious diseases such as COVID-19, where time is critical – the right drug is needed at the right dose immediately.
The relative importance of adult age for successful COVID-19 drug development may depend on the indication – prevention (vaccine), pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), treatment of mild infections, or the treatment of moderate to severe life-threatening infections, including the critically ill. Potentially, different treatment strategies between younger and older adults may be warranted based on safety and tolerability concerns in the non-acute and acute settings. Furthermore, different dosage regimens of effective COVID-19 treatments may be needed, either more aggressive dosing to treat or avoid severe respiratory complications in patients known to have risk factors for poor clinical outcomes, or lower doses to prevent toxicities without compromising efficacy.
Here are a few examples that illustrate clinical pharmacology issues relevant to older patients in some of the well-publicized therapeutic trials for COVID-19.
Tocilizumab is an IL-6 receptor antagonist being studied for the treatment of severe COVID-19 pneumonia (https://clinicaltrials.gov/ct2/show/NCT04320615). The dose previously approved for rheumatology indications (8 mg/kg up to 800 mg maximum) is being used as a single infusion in patients > 18 years old with no upper age limit. The PI for tocilizumab recommends no dose adjustment in those aged 65 years and older. Interestingly, CYP enzyme suppression is caused by pro-inflammatory IL-6, so tocilizumab treatment in rheumatic patients removes a “brake” on drug metabolism that can result in under-exposure of concomitant drugs cleared predominantly by CYP enzymes. Whether the same phenomena occurs in COVID-19 patients in unknown, but this is relevant to the elderly who may survive the infection and
require polypharmacy to maintain control of multiple life-threatening chronic conditions e.g., cardiovascular conditions.
There are many clinical studies with hydroxychloroquine for COVID-19. For example, one study is investigating hydroxychloroquine for PEP at doses of 400 mg daily for 3 days, then 200 mg daily for 11 days (https://clinicaltrials.gov/ct2/show/NCT04328961). Despite being registered since 1955, the molecular determinants of hydroxychloroquine pharmacokinetics are incompletely understood e.g., the contributions of CYP enzymes involved in the generation of active metabolites. Likewise, there is large between patient variability in the steady-state concentrations of hydroxychloroquine, and the covariates that explain this variability are yet to be described adequately. Such gaps in knowledge are particularly problematic in the elderly since hydroxychloroquine has serious dose-related toxicities, including prolonged QT interval, severe hypoglycemia and irreversible retinal damage, for which older patients are especially susceptible.
Lopinavir is an HIV protease inhibitor co-formulated with ritonavir to inhibit CYP3A-mediated gut and hepatic metabolism, thus increasing the oral bioavailability of lopinavir. The combination is currently being investigated as treatment, PrEP and PEP for COVID-19. One study is comparing high-dose lopinavir/ritonavir (800 mg/200 mg) twice daily with placebo as PrEP/PEP in healthcare workers > 18 years of age (https://clinicaltrials.gov/ct2/show/NCT04328285). Loponavir/ritonavir is a significant “perpetrator” of pharmacokinetic drug-drug interactions, but its effects are complex, being concentration and time-dependent. Indeed, it acts as a strong inducer of CYP2C19 but as a strong mechanism-based inhibitor of CYP3A enzymes. Elderly patients have lower clearance of lopinavir/ritonavir compared with younger patients, thus increased risk of usually infrequent AEs such as pancreatitis, and they take more concomitant drugs that are potential “victims” for lopinavir/ritonavir-mediated drug-drug interactions. This could preclude lopinavir/ritonavir as the best therapeutic strategy for PrEP/PEP in certain individuals.
Pharmacotherapy in the elderly poses unique challenges for clinicians and drug developers at the best of times. The swiftness needed to tackle the COVID-19 pandemic adds to this challenge. Integrating knowledge of clinical pharmacology, physiology and the impact of the disease should guide strategies to minimize the risks inherent in this particularly vulnerable patient group. Please continue this discussion in the “Dosing for Special Patient Populations” section of the forum.