Kanarb Mechanism of Action

Pharmacology: Pharmacodynamics: During an in vitro study, fimasartan was found to bind selectively to AT1, which was also demonstrated in non-clinical studies. These findings was also confirmed in phase I and phase IIa clinical studies where ARB-specific changes, such as elevation of plasma renin activity (PRA), increased AI and AII concentrations were identified.
In addition, it has been well established from the results of phase II and III clinical studies that this mechanism of action is associated with the blood pressure lowering effect.
Pharmacokinetics: Absorption: Time to peak plasma concentration (Tmax) following single oral administration of fimasartan at doses of 20-480 mg in healthy subjects ranged 0.5-3 hours with the terminal half-life (t1/2) being 5-16 hours. Similar results were obtained in patients with hypertension, i.e., Tmax ranged 0.5-1.3 hours and t1/2 were 7-10 hours following fimasartan administration at doses 20-180 mg. Several subjects showed a second peak, and the total systemic exposure as assessed by the area under the concentration-time curve was linear (i.e., dose-independent). Accumulation index was 1.20-1.26 and 1.02-1.08 for healthy subjects and patients, respectively. The absolute bioavailability of fimasartan in healthy subjects following 60 mg oral administration compared to 30 mg intravenous infusion was estimated to be 19%.
These results support the notion that oral fimasartan is rapidly absorbed, have linear pharmacokinetic profiles over 20-480 mg doses, and accumulation is minimal when dosed once daily. Therefore, the total systemic exposure can be easily predicted for each dose, which helps increase certainty about the safe and effective use of fimasartan in a clinical setting.
Distribution and Protein Binding: In vitro protein binding in human plasma ranged 95.6-97.2% at fimasartan concentrations of 0.01-100 μg/mL, which was not dose-dependent. These results were similar to those obtained in the dog and rat using the in vitro and ex vivo methods.
Metabolism: In vitro study showed CYP3A4 would be mainly involved in fimasartan metabolism. Fimasartan has not been shown to inhibit or induce other CYP enzymes. The parent drug was ≥85% of the fimasartan moieties found in human plasma with a few metabolites identified, which supports the notion that the pharmacological action of fimasartan is mainly driven by the parent drug. The most abundant circulating metabolites of fimasartan in plasma in healthy male subjects were identified as desulfo-fimasartan and fimasartan-S-oxide. These metabolites accounted for approximately 14% (each 7%) of the total drug related exposure. No parent or metabolite has been assayed in human faeces; however, in vivo metabolism of fimasartan is most likely to be minimal given the systemic exposure level of fimasartan was weakly increased by specific CYP3A4 inhibitors. These favorable pharmacokinetic properties of fimasartan enable its safe use in a clinical setting.
Elimination: Less than 3% of the fimasartan dose was recovered in urine over 24 hours post dose following oral administration in healthy male subjects and patients with hypertension. Therefore, the kidney is unlikely involved in the elimination of fimasartan.
Food Effect: A preliminary exploration was made in a phase I study conducted in the UK for food effect on the pharmacokinetics of fimasartan, and no food effect was noted. A formal food effect study was performed in South Korea, in which the point estimates for the geometric mean ratios of AUC0-∞ and Cmax with and without food were 0.6371 and 0.3481, respectively, suggesting food affects fimasartan's absorption. However, given the exposure-response relationship of fimasartan in reducing blood pressure has been well established and is relatively flat over the therapeutically recommended doses of 60-120 mg, and it took 2-4 weeks to take on drug effect, the observed food effect on the pharmacokinetics of fimasartan is considered insignificant large enough to justify dosage adjustment with food.
Pharmacokinetic Characteristics in special populations: Elderly Subjects: Elderly subjects (i.e., aged ≥65 years old) had a 1.69 times greater systemic exposure than young adults. However, since the renin-angiotensin system (RAS) activity in the elderly is generally lower than young adults, increased systemic exposure will be less likely to result in greater blood pressure reduction. This assumption has been frequently affirmed in other angiotensin receptor blockers. In fact, the blood pressure reduction in elderly subjects enrolled in therapeutic fimasartan clinical trials was numerically smaller than the one seen in those <65 years old. In addition, no difference in the safety profiles was noted between elderly and young subjects. These results collectively support the notion that increased systemic exposure in elderly subjects has less clinical significance, and does not require any dosage adjustment in this population.
Drug Interaction: Pharmacokinetic drug interaction potential for fimasartan was investigated using drugs that may be concomitantly used with fimasartan in diverse clinical settings. Antihypertensive drugs such as hydrochlorothiazide and amlodipine did not show a significant pharmacokinetic interaction with fimasartan. Therefore, fimasartan can be safely co-administered with hydrochlorothiazide and amlodipine without dosage adjustment to achieve further blood pressure reduction in those who do not respond well enough to these antihypertensive medications alone.
Likewise, atorvastatin, digoxin and warfarin, which are frequently used in patients with hypertension, showed no clinically significant pharmacokinetic drug interaction with fimasartan, enabling safe concomitant use without dosage adjustment.
Ketoconazole, a CYP3A4 inhibitor, increased fimasartan's systemic exposure by 2 folds, which is considered weak drug interaction. This magnitude of drug interaction does not require any dosage adjustment for concomitant use, but close monitoring of patients may be recommended. In addition, rifampicin, a strong OATP1B1 inhibitor, increased fimasartan's systemic exposure by 4.6 folds as assessed using AUC. Since OATP1B1 is known to play a significant role in fimasartan's transport into hepatic cells and rifampicin also induces CYP3A4, co-administration of rifampicin with fimasartan is not recommended. Based on these results, fimasartan can be safely co-administered with most drugs in patients with hypertension.
Population Pharmacokinetics: A formal population pharmacokinetic-pharmacodynamic modeling analysis was performed using data obtained from two phase I studies (healthy subjects), conducted in UK, and an early phase II study (patients with mild to moderate hypertension), conducted in South Korea. In addition, a back-of-the-envelope type of population pharmacokinetic analysis was performed using concentrations collected in the ABPM study. Population pharmacokinetic parameters derived from the formal population pharmacokinetic-pharmacodynamic analysis was similar to those estimated using the non-compartment analysis approach. Fimasartan's population pharmacokinetic parameters were not significantly affected by race, sex, or glomerular filtration rate (GFR). Instead, body weight, bilirubin and age were significant covariates. Given that the between-subject variability (BSV) on the fimasartan concentration yielding 50% of the maximal blood pressure reduction (i.e., EC50) was large (i.e., 130-140%), those significant covariates on pharmacokinetic parameters are less likely to affect the extent of blood pressure reduction by fimasartan. Therefore, no dosage adjustment for fimasartan is warranted based on covariates. Similar findings were obtained in the back-of-the-envelope population pharmacokinetic analysis, i.e., height was identified as a significant covariate, but no dosage adjustment based on height is required.
These results support the notion that dosage adjustment for fimasartan based on individual's extrinsic and intrinsic factors is not required to treat patients with hypertension. Rather, dosage adjustment based on treatment response (i.e., blood pressure reduction) will be more practical in a clinical setting.