The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging

Abstract

Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren ® ). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably.

The Effects of Cumulative Dose and Polymorphisms in CYP2B6 on the Mitotane Plasma Trough Concentrations in Chinese Patients With Advanced Adrenocortical Carcinoma

“…It was recommended that mitotane treatment starts at a low dose and gradually increases to the maximum tolerated dose, and the daily dose should not exceed 18 g/day to avoid toxicity ( 36 ). However, it was found that mitotane daily dose was not related to clinically relevant changes in the blood mitotane level in our study, even if the difference in the blood mitotane concentration was statistically significant, which is consistent with previous results ( 18 ). In addition, we found no associations of age, weight, height, age of ACC diagnosis, and treatment time initial date with blood mitotane concentrations and no drug interaction between mitotane and inhibitors of CYP enzymes or antacids.…”

“…According to previous studies, cumulative dose on mitotane concentration is still controversial. The results of a small prospective and multicenter study involving 40 ACC patients, grouped to a low-dose or high-dose mitotane regimen, showed that, despite there being a difference in the average cumulative dose between the two groups, the median maximum plasma concentrations were not significantly different ( 18 ). Other literature confirmed a significant correlation of the cumulative dose of mitotane and the highest plasma mitotane trough level ( 13 .…”

“…In particular, the cumulative dose has been shown a higher risk of mitotane accumulation in the Caucasian population, which explains 35% of the variability in the plasma mitotane level (13). Whereas other studies have shown that the level of mitotane has a poor correlation with administration dosage indicates that there are other factors that may affect the target concentrations of mitotane (17,18). In addition, sex differences in mitotane concentration are still controversial (15,19), and the unexplained pharmacokinetic variability of mitotane remains high.…”

Advanced Adrenocortical Carcinoma: From Symptoms Control to Palliative Care

“…Mitotane treatment is started as soon as possible after surgery [ 5 ] with a low-dose (3 g/day after 12 days) or high-dose (3 g/day after 2 days, 6 g/day after 12 days) regimen, achieving similar plasma levels and demonstrating similar onset of adverse events [ 15 ]. Some patients do not achieve the therapeutic plasma concentration of 14–20 mg/L in the follow-up, even at doses up to 6–7 g/day (12–14 tablets in divided doses), due to poor water solubility, the large volume of distribution, the onset of adverse effects and inter/intra-individual variability [ 16 ]. Moreover, it has been found that 40% of unchanged mitotane could be detected in the feces 12 h after an oral intake of a single 2 g mitotane dose in tablet form [ 17 ].…”

“…Moreover, it has been found that 40% of unchanged mitotane could be detected in the feces 12 h after an oral intake of a single 2 g mitotane dose in tablet form [ 17 ]. The most common mitotane-induced side effects in patients with ACC are gastrointestinal disturbances, neurologic symptoms, leukopenia and hepatic disorder (liver failure is rare; however, asymptomatic increases in hepatic enzymes—in particular, gamma-GT—are common) [ 5 ], alone or combined: they represent a major limit to treatment adherence [ 15 , 16 , 17 ]. Novel oral (recrystallization from microemulsion, nanosuspension, liposomal) and injectable (micellar) formulations are currently being developed in order to improve the efficacy and tolerability of mitotane [ 16 ].…”