Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effect of Renal Impairment on the Pharmacokinetics of Olanzapine and Samidorphan Given in Combination

Separate PBPK models for olanzapine and samidorphan were developed in the Simcyp Simulator (Certara, Princeton, NJ, USA) as described previously [22]. Briefly, a minimal PBPK model was used for olanzapine that included a single adjusting compartment combining all tissues except the intestine, liver, and portal vein (Fig. 2a). A full PBPK model, which included additional tissues such as adipose, brain, bone, heart, lung, muscle, and skin, was used for samidorphan (Fig. 2b). These models were selected because they described the disposition of each component of OLZ/SAM with reasonable accuracy when compared with existing clinical data. A minimal PBPK model was adequate for describing the disposition of olanzapine, while a full PBPK model led to improved recovery of the observed half-life of samidorphan. The input parameters for each model have been previously described [22] and are presented in Table 1. These parameters take into account available in vitro metabolism and in vivo clinical data, such as plasma protein binding, Caco-2 cell permeability, interaction with P-glycoprotein, absorption rate kinetics, enzyme effects, and other pharmacokinetic data [23‐26]. Both olanzapine and samidorphan were assumed to have first-order absorption kinetics, as first-order models were able to capture the absorption profiles of both olanzapine and samidorphan adequately.

Elevated serum creatinine levels indicate varying levels of RI [27]. Within the Simcyp Simulator, a serum creatinine value (µmol/L) was generated for each individual from a log-normal distribution defined by a mean and coefficient of variation (depending on the RI category). This value was then used in the Cockcroft–Gault equation to estimate creatinine clearance (mL/min). The creatinine clearance was divided by a value of 120 or 130 for female and male patients, respectively, to determine a scalar of renal function, which was then applied directly to the renal plasma clearance input. A mean serum creatinine level of 105 µmol/L (with a corresponding coefficient of variation of 9%) was applied to generate appropriate levels in a population with mild RI [27]. The corresponding parameters for moderate and severe RI were the default values of the Sim-RenalGFR_30–60 and RenalGFR_less_30 populations, respectively (Table 2).

Anemia develops as a consequence of CKD, and decreased hemoglobin and/or hematocrits have been reported for male and female patients with CKD [28, 29]. For mild RI, moderate RI, and severe RI, hematocrit values of 39.7%, 39.7%, and 33.2% were applied to male patients, respectively, and hematocrit values of 36.5%, 36.5%, and 31.3% were applied to female patients, respectively (Table 2) [28, 29].

Changes in drug plasma protein binding are often observed in mild, moderate, and severe RI owing to decreased levels of albumin (a direct consequence of hyperalbuminuria in subjects with CKD) or an increase in plasma levels of alpha acid glycoprotein [30]. Within the Simulator, depending on the main binding protein, the generated albumin or alpha acid glycoprotein levels ([P]) for a disease population may be used against a reference value for healthy subjects ([P]_pop) to calibrate the fraction unbound (fu) for the latter (fu_pop) to a disease population value (fu), according to the following equation:

The default values of the healthy volunteer library were used for the generation of albumin levels in virtual subjects with mild RI. The corresponding parameters for moderate and severe RI were the default values of the Sim-RenalGFR_30–60 and RenalGFR_less_30 populations, respectively. For both samidorphan and olanzapine, it was assumed that the main binding protein was albumin [11]. Albumin levels for subjects with normal RF and with mild, moderate, and severe RI are shown in Table 2.

Non-renal clearance of drugs consists largely of hepatic metabolism mediated by CYP and UGT enzymes. Although hepatic enzyme expression data in subjects with RI are not available, abundance values have been extrapolated using clinical data from patients with mild, moderate, or severe RI (Table 2) [19, 31]. The default values in the Simcyp Simulator for CYP1A2, CYP2C8, and CYP3A4 in the moderate and severe RI populations were applied in all simulations. Sayama and colleagues analyzed data for 151 drugs in subjects with moderate and severe RI to derive scalars for changes in non-renal clearance via CYP and UGT-mediated metabolism and via other undisclosed mechanisms [31]. Median scalars of 0.68 and 0.65 were reported for changes in CYP-mediated hepatic metabolism for patients with moderate and severe RI relative to healthy subjects, respectively. Corresponding values of 0.67 and 0.59 were reported for median changes in UGT metabolism. These latter values were applied to hepatic UGT1A4 abundance values of 52 pmol/mg protein in healthy subjects to obtain estimates of 34.8 and 30.7 pmol/mg protein in moderate and severe RI, respectively. The CYP3A4 abundances for a population with mild RI based on extrapolation from clinical data (nifedipine, rivaroxaban, reboxetine, tolvaptan, tadalafil, and eplenerone) were estimated to be 120.9 pmol/mg protein (0.88 of the baseline value in healthy subjects). Thus, this scalar was applied to obtain estimates of CYP1A2, CYP2C8, and UGT1A4 abundances in subjects with mild RI. The changes in enzyme abundance levels and in other parameters that were used in the simulations of subjects with RI are shown in Table 2.

The PBPK model for OLZ/SAM was previously validated by comparing simulated plasma C–T profiles and pharmacokinetic parameters of olanzapine and samidorphan with observed clinical data following a single dose of OLZ/SAM 10 mg/10 mg (10/10) in healthy subjects [14, 32], and following multiple once-daily doses of OLZ/SAM 10/10 for 14 days in patients with schizophrenia [13]. Additional model validation was conducted by comparing model-simulated C‐T profiles and pharmacokinetic parameters of olanzapine and samidorphan, including the C_max, AUC, and apparent clearance, with observed data from the clinical study evaluating the impact of severe RI on the pharmacokinetics of olanzapine and samidorphan [16]. Virtual trials were generated to match subject demographics (i.e., age and sex) and treatment characteristics of the clinical study [16]: ten trials of ten subjects with severe RI (30% female; aged 38–72 years) receiving a single dose of OLZ/SAM 5/10, and ten trials of ten healthy controls with normal renal function (30% female; aged 59–73 years) receiving a single dose of OLZ/SAM 5/10. Simulated values for healthy subjects, with the exception of demographic data, were derived from a Caucasian population using default Simcyp parameter values.

The validated model was applied to predict changes in steady-state systemic exposures of olanzapine and samidorphan after multiple once-daily administration of OLZ/SAM 10/10. Each simulation consisted of ten virtual trials of ten subjects each (30% female; aged 38–72 years) in the following groups: (1) subjects with mild RI; (2) subjects with moderate RI; (3) subjects with severe RI; and (4) healthy control subjects with normal renal function, based on the following definitions of renal function: normal (estimated glomerular filtration rate [eGFR] of ≥ 90 mL/min/1.73 m²), mild RI (eGFR of ≥ 60 to < 90 mL/min/1.73 m²), moderate RI (eGFR of ≥ 30 to < 60 mL/min/1.73 m²), and severe RI (eGFR of ≥ 15 to < 30 mL/min/1.73 m²).

Model-simulated mean plasma C–T profiles and pharmacokinetic parameters of olanzapine and samidorphan in subjects with severe RI and healthy controls after a single dose of OLZ/SAM 5/10 were consistent with observed data [16] (Fig. 3; Table 3). A high intersubject variability in the pharmacokinetic profiles of olanzapine and samidorphan was noted in subjects with RI (Fig. 3a, c) compared with the healthy controls (Fig. 3b, d). This is likely caused by alterations in drug bioavailability and clearance owing to chronic renal disease and/or potential pharmacokinetic interactions with concomitant medications received by subjects with renal impairment [16]. The effects of severe RI on the pharmacokinetics of olanzapine and samidorphan observed in the clinical study [16] were well predicted (Table 4). Based on geometric mean data, the model predicted a 1.5-fold increase in the total exposure (AUC_0–∞) of olanzapine in subjects with severe RI compared with healthy controls, which was consistent with the 1.5-fold increase observed in the clinical study [16]. Similarly, the model predicted a 2.2-fold increase in the AUC_0–∞ of samidorphan in subjects with severe RI, consistent with the 2.3-fold increase observed in the clinical study [16]. Model-predicted reductions of 38% and 54% in olanzapine and samidorphan total clearance, respectively, in subjects with severe RI, were also consistent with the reductions of 33% and 56%, respectively, observed in the clinical study [16].

Simulated steady-state plasma C–T profiles of olanzapine and samidorphan in subjects with mild, moderate, or severe RI compared with healthy, age-matched control subjects after once-daily administration of OLZ/SAM 10/10 for 14 days are depicted in Fig. 4a, b. Model-predicted steady-state maximum plasma concentration (C_max,ss) and area under the C–T curve over the 24-hour dosing interval (AUC_τ,ss) of olanzapine and samidorphan in subjects with mild, moderate, or severe RI compared with healthy controls are presented in Table 5. Physiologically based pharmacokinetic predictions indicated that C_max,ss and AUC_τ,ss of olanzapine and samidorphan increased consistently as the severity of RI increased. Compared with subjects with normal renal function, an increase in AUC_τ,ss was predicted to be < 1.5-fold for both olanzapine and samidorphan in subjects with mild RI, 1.5-fold for olanzapine, and 1.8-fold for samidorphan in subjects with moderate RI, and 1.6-fold for olanzapine and 2.2-fold for samidorphan in subjects with severe RI. The increase in C_max,ss was predicted to be up to 1.5-fold higher for both olanzapine and samidorphan in subjects with severe RI.