In this perspective, we highlight the significant global disparities encountered since the introduction of elexacaftor/tezacaftor/ivacaftor, which have largely excluded the cystic fibrosis population in low to middle income countries. We propose a pharmacokinetic (PK) enhancement strategy developed using physiologically-based pharmacokinetic (PBPK) modeling, to mitigate the high cost of treatment. The aim of this paper is to raise awareness of global monopoly concerns and provide a clinical practice strategy to effectively address the issue. Over the past decade, the therapeutic landscape for cystic fibrosis (CF) has undergone a discernible shift, progressing from interventions targeting the secondary consequences of the disease to interventions directed toward restoration of cystic fibrosis transmembrane conductance regulator (CFTR) function with the advent of CFTR modulators. The most recent of these—the triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI, TRIKAFTA)—is suitable for a larger proportion of mutation profiles compared with previous generations. Recent trials showed an impressive clinical effect of ETI triple combination therapy, which led to significant improvements in lung function and nutritional status in people with CF.1 Since approval in October 2019, ETI has been prescribed in 90% of people with CF in high-income countries, whereas it remains inaccessible in most low-and middle-income countries (LMICs) due to a combination of factors, such as the absence regulatory approval and high cost. CFTR modulators are protected from competition by restrictive patents worldwide, hindering the importation of generics into LMICs, many of which are still awaiting the registration of the original drugs. The extreme cost of CFTR modulators have widened existing global health disparities.2 The delayed access to ETI is anticipated to have adverse consequences on lung health and overall survival within the CF population.3 The early introduction of ETI was projected to reduce the number of individuals with severe lung disease by 60%, reduce deaths by 15%, and improve the median age of survival by 9.2 years.3 Considering the patent for ETI is anticipated to remain until 2037, the drug will remain beyond the reach of patients outside of the world's wealthiest countries without proactive intervention. Even within high income countries, patients are at risk for losing access to ETI due to restricted formularies imposed by payors in response to the high cost of this therapy.4 Given that all three components of ETI are extensively metabolized by cytochrome P450 3A (CYP3A), the PK enhancement strategy is a potential approach to reduce the drug dosage and corresponding drug costs. Ritonavir is frequently used as a PK booster for drugs undergoing rapid degradation by CYP3A, prolonging the half-life and therapeutic efficacy, as in the treatment of HIV (e.g., darunavir/ritonavir) and more recently coronavirus disease 2019 (COVID-19; Paxlovid or nirmatrelvir/ritonavir). The ritonavir boosting strategy has been reported to enhance the efficacy of antiretroviral therapy for HIV-infected patients with prior failure of protease inhibitors. Multiple clinical studies as well as PBPK simulations have been conducted for CFTR modulators to determine the interaction profile and appropriate dose adjustments to mitigate drug–drug interactions (DDIs) with strong CYP3A inhibitors. Leveraging this extensive dataset, we present practical recommendations for the judicious reduction of ETI doses with enhancer agents and the principles that guided these recommendations. This strategic approach aims to establish a cost-effective ETI regimen that could incentivize payors to support increased access to CFTR modulators worldwide. Numerous clinical investigations have elucidated significant drug interactions involving ETI with potent CYP3A inhibitors. Especially, as potent mechanism-based inhibitors of CYP3A, clarithromycin and ritonavir cause irreversible inhibition by forming a metabolic intermediate complex, inactivating CYP3A, which requires replacement via newly synthesized enzyme. In the case of clarithromycin, a study involving clarithromycin 500 mg twice daily administered for 2.5 days resulted in a 3-fold increase in area under the curve (AUC) of ivacaftor.5 A PBPK simulation study reported that the predicted steady-state AUC ratio of elexacaftor, tezacaftor, and ivacaftor when co-administered with clarithromycin 500 mg twice daily were 2.43 (90% confidence interval: 2.27–2.59), 2.92 (2.73–3.12), and 9.64 (8.33–11.16), respectively.6 There is a preference to select clarithromycin in the context of CF where long-term macrolide pharmacotherapy is established practice for its immunomodulation and anti-inflammatory effects. However, long-term use of macrolides may increase the risk of inducing macrolide resistance in colonizing CF bacteria, including non-tuberculous mycobacteria. Co-administration with ritonavir 100 mg twice daily for 3.5 days elevated ivacaftor exposure by 6.6-fold in individuals with CF and 8.9-fold in healthy volunteers, with no significant differences between the groups (P = 0.47).5 A PBPK simulation study of ritonavir 100 mg twice daily administered for 5 days (following the suggested regimen of nirmatrelvir-ritonavir) reported that the predicted AUC ratios of elexacaftor, tezacaftor, and ivacaftor were 2.31 (2.20–2.42), 3.11 (2.96–3.27), and 9.31 (8.28–10.47) respectively.7 Given the substantial increase in ETI concentrations when co-administered with potent CYP3A inhibitors, a boosting strategy may be used for ETI to reduce drug cost. The application of PBPK modeling results can inform the optimized dosing strategies for ETI and the PK enhancer. For clarithromycin (500 mg twice daily), administration of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg every 3 days provides similar PK exposure to standard dose ETI administered alone6 (Table 1). Utilizing the published PBPK models of ritonavir-ETI,7 it is demonstrated that ETI can be administered twice weekly (e.g., Mondays and Fridays) with ritonavir 100 mg 3 times weekly (e.g., Mondays, Wednesdays, and Fridays). These findings underscore ritonavir's sustained and more potent inhibition than that of clarithromycin. The reduced ritonavir dosage aligns partially with the ETI dosing schedule and is projected to maintain ETI levels above the reported plasma efficacy parameters (Table 1). The cost-effectiveness of ETI has been extensively evaluated by the Institute for Clinical and Economic Review (ICER).8 Results of their analyses showed that CFTR modulator therapies plus best supportive care substantially improves patient health outcomes compared with best supportive care. However, the cost-effectiveness of CFTR modulator therapies ($1.1 to $1.5 million per quality-adjusted life year (QALY)) exceeds commonly used cost-effectiveness thresholds (e.g., $100,000 to $150,000 per QALY or equal value life year gained). ICER's recommended health-benefit price benchmark (HBPB) for ETI was determined to be $67,900–$85,500 per year (2020), which would require at least a 73% discount off the treatment's list price ($311,700 in 2020). The HBPB is a price range suggesting the highest US price a manufacturer should charge for a treatment, based on the amount of improvement in overall health patients receive from that treatment, when a higher price would cause disproportionately greater losses in health among other patients in the health system due to rising overall costs of health care and health insurance. Analysis of real-world data from a payor perspective similarly demonstrates the high cost of ETI therapy relative to short-term health outcomes. Marshall and colleagues performed a retrospective evaluation of pharmacy and medical claims data to determine the cost of care and healthcare resource utilization 6 months before and following initiation of ETI among a commercially insured CF (n = 494).9 The prestudy to poststudy mean member total cost of care increased from $58,180 to $198,815 (difference $140,635, P < 0.001). Although the medical benefit costs were significantly reduced (mean difference − $16,280, P < 0.001), these reductions were more than offset by the significantly increased pharmacy benefit costs (mean difference + $156,915, P < 0.001). One potential strategy to reduce the ETI cost is through PK enhancement. The recommended dose of ETI in the presence of a strong CYP3A inhibitors to reduce administration to elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg twice weekly in adults. Using the branded product (Trikafta, $325,300 annually), the cost with the reduced dose would be $92,943 which approximates the HBPB ($78,744 to $99,155 accounting for inflation) and therefore provides a more favorable price from the payor's perspective. Notably, in regions where ETI is unavailable, some patients have obtained generic ETI from Argentina (on a named patient import basis), to reduce the overall drug costs.10 The cost of reduced dose using the generic product (Trixacar, $58,800 annually), would be $16,800 which is substantially below the HBPB. Real-world efficacy and safety of generic ETI alone (n = 31) or in combination with the PK enhancer clarithromycin (n = 12) was evaluated in 43 individuals with CF from South Africa.10 Generic ETI (Gador S.A., Buenos Aires, Argentina) was administered as "standard" (i.e., elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening daily) or "modulator sparing" twice weekly dosing (i.e., elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning) when co-administered with clarithromycin 250–500 mg twice daily. Forced expiratory volume 1.0 second % (FEV1%) predicted improved significantly (+15.1, P < 0.01), whereas sweat chloride notably decreased (mean ± SD, −44 ± 21 mmol/L), and no statistical differences in FEV1 improvement as well as sweat chloride reduction were observed between dosing groups. These data provide preliminary evidence of the efficacy of PK enhanced ETI therapy as a feasible approach to achieving cost-effective CFTR modulator therapy for people with CF. The health benefits associated with ETI therapy are well-substantiated; however, the lack of access to this vital therapy in LMIC is leading to significant global disparities in health outcomes for people with CF. In this report, we provide guidance on dose adjusted ETI therapy using PK enhancers to mitigate the high cost of treatment. The concomitant administration of ritonavir or clarithromycin allow significant reduction in the ETI dose to twice weekly resulting in a cost-effective therapy which approximates the HBPB. Moreover, the PBPK approach predicts that in case of ritonavir, the dosage for not only ETI but also the enhancer could be further reduced, attributed to sustained and potent CYP3A inhibitions. Further reductions in cost can be achieved with use of generic ETI formulations where they are available. Potential drawbacks of PK enhanced ETI include DDIs between PK enhancers and other concomitant medications, adverse reactions due to the PK enhancer, and additional costs for the PK enhancer. A comprehensive medication review should be performed prior to initiation of the PK enhancer to identify and address any potential drug interaction. The risk of adverse reactions with ritonavir should be low due to the low dose needed based on the PBPK simulations. Because both clarithromycin and ritonavir are available in generic forms the costs are low relative to the cost savings from ETI. The positive results of preliminary real-world use of ETI with concomitant clarithromycin justify the need for definitive clinical trials evaluating the PKs, efficacy, safety, and cost-effectiveness of PK enhanced ETI therapy. No funding was received for this work. The authors declared no competing interests for this work.
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