Physiologically Based Pharmacokinetic Modeling to Understand the Observed Drug–Drug Interaction of LY2623091 with CYP3A Inhibitors Itraconazole and Diltiazem

Figures & data

Table 1. In silico simulation design for the evaluation of the impact of CYP3A4 inhibition on the pharmacokinetics of LY2623091 using Simcyp.

	Substrate LY2623091	Inhibitor itraconazole	Inhibitor diltiazem
Route	Oral	Oral	Oral
Dose	6 mg	200 mg BID on day 1 200 mg QD on days 2-20	240 mg QD
Start time	0900 day 6 (group 1) 0900 day 4 (group 2)	1000 day 6	0900 day 4
Dosing regimen	Single	Multiple	Multiple
Dosing interval	Single dose	12 h on day 1 24 h on days 2-20	24 h
Number of doses	1	21	13
Population selected	Simcyp^® healthy volunteer population
Population size	100
Number of trials	10
Number of subjects per trial	10
Fasted/Fed	Fasted

BID: Twice a day; CL_int: Intrinsic clearance of drug in an eliminating organ; fa: Fraction absorbed from the gut lumen into the gut wall; fumic: Fraction unbound in microsome; fuP: Fraction unbound in plasma; HLM: Human liver microsome; ka: Absorption rate constant; LogP: Measure of lipophilicity; MW: Molecular weight; P_eff: Effective permeability; pKa: Measure of ionization; QD: Once a day; RAF: Relative activity factor; V_ss: Volume of distribution under steady state conditions.

Table 2. Drug-specific assumption of parameters of LY2623091 used to construct the physiologically based pharmacokinetic model.

Relevant Property	Parameter	LY2623091	Source
PhysChem and Blood Binding	MW (g/mol)	528
	LogP	4.89	Measured in-house
	pKa (basic)	6.01	Measured in-house
	B:P	1	Assumption based on compound type
	fuP	0.002	Measured in-house
Absorption	Model	1st Order
	Peff (x 10^−4 cm/s)	4	Estimated using in house model
	Fa	0.98	Predicted within Simcyp^®
	ka (h^−1)	1.6	Predicted within Simcyp
Distribution	Model	Minimal PBPK Model
	Vss (l/kg)	0.52	From clinical study assuming F = 1
Elimination	Approach	Enzyme Kinetics	HLMs
	CLint CYP3A4 (µl/min/pmol isoform)	367	Measured in recombinant systems and scaled to HLMs using in-house RAFs
	CLint CYP2J2 (µl/min/pmol isoform)	1.8
	fumic	1	Measured in-house

B:P: Blood to plasma concentration ratio; CL_int: Intrinsic clearance of drug in an eliminating organ; fa: Fraction absorbed from the gut lumen into the gut wall; fu_mic: Fraction unbound in microsomes; fu_P: Fraction unbound in plasma; HLM: Human liver microsome; ka: Absorption rate constant; LogP: Measure of lipophilicity; MW: Molecular weight; PBPK: Physiologically based pharmacokinetic; P_eff: Effective permeability; pKa: Measure of ionization; RAF: Relative activity factor; V_ss: Volume of distribution under steady-state condition.

Table 3. Observed and predicted pharmacokinetic parameters for LY2623091, itraconazole, and hydroxy-itraconazole and observed and predicted interaction ratios for LY2623091 in the presence of itraconazole and diltiazem.

Analyte	Parameter	Observed	Predicted (mean)^†	Pred/Obs
LY2623091	Cmax (ng/ml)	61.9*	75.1	1.2
	AUC(0-∞) (ng.h/ml)	2465*	1378	0.6
	Cmax ratio (itraconazole)	1.08	2.0	1.9
	AUC ratio (itraconazole)	2.23	9.8	4.4
	Cmax ratio (diltiazem)	1.04	1.4	1.3
	AUC ratio (diltiazem)	1.37	2.9	2.1
Itraconazole	Cmax,ss (ng/ml)	1900	1620	0.85
	AUC(0-T) (ng.h/ml)	21,300	11,159	0.52
Hydroxy-itraconazole	Cmax,ss (ng/ml)	1560	799	0.51
	AUC(0-T) (ng.h/ml)	31,700	17,563	0.55

^†Predicted data are mean values; observed C_max and AUC values are geometric means; Observed ratios are the ratio of the geometric least squares mean.

AUC_(0-T): Area under the concentration time curve over the dosing interval at steady state; AUC_(0-∞): Area under the concentration time curve from time zero to infinity; C_max: Maximum concentration; C_max,ss: Maximum plasma concentration at steady state; Obs: Observed; Pred: Predicted.

*Average of group 1 and group 2 mean values.

Figure 1. Observed and predicted LY2623091 plasma concentrations in the presence and absence of itraconazole.

Red lines represent simulations; black lines show the observed data with the error bars representing the 90% confidence interval.

Figure 2. Plasma concentrations demonstrating predicted and observed accumulation in exposure to itraconazole and hydroxy-itraconazole.

Red lines represent simulations; black lines represent observed data with the error bars representing the 90% confidence interval.

Figure 3. Simulated area under the concentration–time curve ratios for itraconazole and diltiazem, assuming various values of fm.

AUCR: Area under the concentration–time curve ratio; DIL: Diltiazem; fm: Fraction metabolized; ITR: Itraconazole.

Figure 4. Proposed metabolic pathways and plasma metabolites for LY2623091 in healthy human subjects.

F: Feces; P: Plasma.

Table 4. Observed and predicted pharmacokinetic parameters for LY2623091, itraconazole, and hydroxy-itraconazole and observed and predicted interaction ratios for LY2623091 in the presence of itraconazole and diltiazem.

Analyte	Parameter	Observed	Predicted (mean)	Pred/Obs
LY2623091	Cmax (ng/ml)	61.9^†	75.1	1.2
	AUC(0-∞) (ng.h/ml)	2465^†	1378	0.6
	Cmax ratio (itraconazole)	1.08	2.0	1.9
	AUC ratio (itraconazole)	2.23	9.8	4.4
	Cmax ratio (diltiazem)	1.04	1.4	1.3
	AUC ratio (diltiazem)	1.37	2.9	2.1
Itraconazole	Cmax,ss (ng/ml)	1900	1620	0.85
	AUC(0-T) (ng.h/ml)	21,300	11,159	0.52
Hydroxy-itraconazole	Cmax,ss (ng/ml)	1560	799	0.51
	AUC(0-T) (ng.h/ml)	31,700	17,563	0.55

^†Average of group 1 and group 2.

AUC_(0-T): Area under the concentration time curve over the dosing interval at steady state; AUC_(0-∞): Area under the concentration time curve from time zero to infinity; C_max: Maximum concentration; C_max,ss: Maximum plasma concentration at steady state; Obs: Observed; Pred: Predicted.