Cinakalcet

Additional information

Pharmacokinetics and dosing

According to the pharmaceutical company, a population based pharmacokinetic analysis did not show any clinically significant effect of patient’s sex on cinacalcet pharmacokinetics [1]. Pooled data from 9 clinical studies (80 women, 154 men) did not show any clinical significance of patient’s sex on cinacalcet exposure [2]. However, women had on average 29% higher cinacalcet AUC than men. Apparent clearance was observed to be 40% lower in women than in men, though it is unclear whether clearance was studied in patients or in healthy subjects [2]. Nevertheless, no dose adjustment based on patient’s sex is required as doses are titrated individually [1].

Some sex difference in pharmacokinetics may be partially attributed to the known sex difference in CYP1A2 expression [3].

Effects

Cinacalcet normalizes serum calcium in both men and women with primary hyperparathyroidism (pHPT), according to two small randomized studies (ca 100 patients, predominantly in women) and a small retrospective study consisted mostly of men (16 men, 2 women) [4].

Analysis of combined data of three placebo-controlled phase III randomized trials of cinacalcet in secondary HPT (sHPT) in dialysis patients showed that 46% of men (187/407) and 38% of women (97/258) (no statistically significant sex difference) achieved the primary endpoint (proportion of patients with intact parathyroid hormone (iPTH)≤250 pg/mL) [5]. In one of three studies (181 men, 113 women) there were 40% cinacalcet treated men versus 27% women that achieved iPTH≤250 pg/mL. Notably, at the baseline in this study more women than men (45% women vs 37% men) had iPTH>800 pg/mL which could have affected results [6].

Adverse effects

In a 6-month phase III trial comparing cinacalcet with placebo for treatment of end-stage renal disease (ESRD) (244 men, 148 women), neither men nor women had an effect on T4/TSH [6].

Cholelithiasis is considerably more common in women and is a common complication of HPT. Small cross-sectional study in hemodialysis (HD) patients (15 men, 8 women) demonstrated that gastrointestinal (GI) adverse events of cinacalcet were more frequent in the HD patients with gallstones than without gallstones (OR 13.5, 95% CI: 1.80–101). However, there was no association of patient’s sex with the incidence of GI adverse events in the cinacalcet group [7].

Reproductive health considerations

The pharmaceutical company reports reduced levels of testosterone but unchanged LH and FSH level in men with ESRD treated with cinacalcet for 6 months [6,1,8]. The clinical significance of this effect on testosterone is not known [1]. No further decrease in free and total testosterone in cinacalcet treated patients was found over 3 years in an open-label extension of the study [1].

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Female sex is suggested to be one of the risk factors for developing calciphylaxis, also called calcific uremic arteriolopathy (CUA), in patients with advanced chronic kidney disease (CKD) and ESRD. The EVOLVE trial compared cinacalcet with placebo (3883 hemodialysis patients, 40% women) in sHPT [9]. There were 6 cases of CUA (2 men, 4 women) among patients receiving cinacalcet and 18 cases (7 men, 11 women) CUA in patients receiving placebo. Male sex was proposed to be a protective factor towards developing CUA. Analysis of the EVOLVE trial data suggested treatment effect of cinacalcet on clinical fracture only in women (0.66, 95% CI 0.49-0.90) but not in men (0.79, 95% CI 0.58-1.07) [10]. The relative hazard of severe unremitting HPT in the EVOLVE trial was 0.31 (95% CI 0.26-0.37) and the effect was similar in men and women [11].