Pasireotide

Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like the natural peptide hormones somatostatin-14 and somatostatin-28 (also known as somatotropin release inhibiting factor [SRIF]) and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding to somatostatin receptors. Five human somatostatin receptor subtypes are known: hsst1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogues bind to hsst receptors with different potencies. Pasireotide binds with high affinity to four of the five hssts.

Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotide to the five human somatostatin receptor subtypes (hsst1-5):

Results are the mean±SEM of IC₅₀ values expressed as nmol/l.

Pharmacodynamic effects

Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which hormones are excessively secreted, including ACTH in Cushing’s disease.

In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display a high expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressed at lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophs of ACTH-producing adenomas, resulting in inhibition of ACTH secretion.

Pasireotide for intramuscular use is formulated as microspheres for long-acting release. After a single injection, the plasma pasireotide concentration shows an initial burst release on the injection day, followed by a dip from day 2 to day 7, then a slow increase to maximum concentration around day 21, and a slow declining phase over the next weeks, concomitant with the terminal degradation phase of the polymer matrix of the dosage form.

Absorption

In healthy volunteers, pasireotide subcutaneous use is rapidly absorbed and peak plasma concentration is reached within 0.25-0.5 h. C_max and AUC are approximately dose-proportional following administration of single and multiple doses.

The relative bioavailability of pasireotide intramuscular use over pasireotide subcutaneous use is complete. No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans.

Distribution

In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (V_z/F >100 litres). Distribution between blood cells and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.

Based on in vitro data pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein). Based on in vitro data pasireotide is not a substrate of the efflux transporter BCRP (breast cancer resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organic anion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not an inhibitor of UGT1A1, OATP, 1B1 or 1B3, P-gp, BCRP, MRP2 and BSEP.

Biotransformation

Pasireotide is metabolically highly stable and in vitro data show that pasireotide is not a substrate, inhibitor or inducer of any major enzymes of CYP450. In healthy volunteers, pasireotide is predominantly found in unchanged form in plasma, urine and faeces.

Elimination

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion), with a small contribution of the renal route. In a human ADME study 55.9±6.63% of the radioactive dose was recovered over the first 10 days after administration, including 48.3±8.16% of the radioactivity in faeces and 7.63±2.03% in urine.

Pasireotide demonstrates low clearance (CL/F ~7.6 litres/h for healthy volunteers and ~3.8 litres/h for Cushing’s disease patients). Based on the accumulation ratios of AUC, the calculated effective half-life (t_1/2,eff) in healthy volunteers was approximately 12 hours.

Linearity and time dependency

In Cushing’s disease patients, pasireotide subcutaneous use demonstrates linear and time-independent pharmacokinetics in the dose range of 0.3 mg to 1.2 mg twice a day. Population pharmacokinetic analysis suggests that based on C_max and AUC, 90% of steady state in Cushing’s disease patients is reached after approximately 1.5 and 15 days, respectively.

Pharmacokinetic steady state for pasireotide intramuscular use is achieved after three months. Following multiple monthly doses, pasireotide intramuscular use demonstrates approximately dose-proportional pharmacokinetic exposures in the dose range of 10 mg to 60 mg every 4 weeks.

Special populations

Paediatric population

No studies have been performed in paediatric patients.

Patients with renal impairment

Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical study with single subcutaneous dose administration of 900 μg pasireotide in subjects with impaired renal function, renal impairment of mild, moderate or severe degree, or end stage renal disease (ESRD) did not have a significant impact on total pasireotide plasma exposure. The unbound plasma pasireotide exposure (AUC_inf,u) was increased in subjects with renal impairment (mild: 33%; moderate: 25%, severe: 99%, ESRD: 143%) compared to control subjects.

Patients with hepatic impairment

No clinical studies in subjects with liver impairment have been performed with pasireotide intramuscular use. In a clinical study of a single subcutaneous dose of pasireotide in subjects with impaired hepatic function, statistically significant differences were found in subjects with moderate and severe hepatic impairment (Child-Pugh B and C). In subjects with moderate and severe hepatic impairment, AUC inf was increased 60% and 79%, C_max was increased 67% and 69%, and CL/F was decreased 37% and 44%, respectively.

Elderly patients (≥65 years)

Age has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s disease patients. Decreased total body clearance and increased pharmacokinetic exposures have been seen with increasing age. In the studied age range 18-73 years, the area under the curve at steady state for one dosing interval of 12 hours (AUC_ss) is predicted to range from 86% to 111% of that of the typical patient of 41 years. This variation is moderate and considered of minor significance considering the wide age range in which the effect was observed.

Data on Cushing’s disease patients older than 65 years are limited but do not suggest any clinically significant differences in safety and efficacy in relation to younger patients.

Demographics

Population pharmacokinetic analyses of pasireotide subcutaneous use suggest that race and gender do not influence pharmacokinetic parameters. Body weight has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s disease patients. For a range of 60-100 kg the reduction in AUC ss with increasing weight is predicted to be approximately 27%, which is considered moderate and of minor clinical significance.

Population PK analyses of pasireotide intramuscular use suggest that race does not influence PK parameters. PK exposures had a slight correlation with body weight in the study with medical treatment naïve patients, but not in the study with inadequately controlled patients. Female acromegaly patients had a higher exposure of 32% and 51% compared to male patients in studies with medical treatment naïve patients and inadequately controlled patients, respectively; these differences in exposure were not clinically relevant based on efficacy and safety data.

Non-clinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of pasireotide. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Pasireotide was not genotoxic in in vitro and in vivo assays.

Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenic potential.

Pasireotide did not affect fertility in male rats but, as expected from the pharmacology of pasireotide, females presented abnormal cycles or acyclicity, and decreased numbers of corpora lutea and implantation sites. Embryo toxicity was seen in rats and rabbits at doses that caused maternal toxicity but no teratogenic potential was detected. In the pre- and postnatal study in rats, pasireotide had no effects on labour and delivery, but caused slight retardation in the development of pinna detachment and reduced body weight of the offspring.

Available toxicological data in animals have shown excretion of pasireotide in milk.