Table 3.

Mean olaparib tablet or capsule AUC and C_max ratios from PBPK model simulations investigating the effect of hepatic or renal impairment

Type and severity of impairment	Study simulation parameters required for dose adjustment recommendation	Observed exposure ratiod, 13				Predicted exposure ratio
		AUC ratio (90% CI)	Cmax ratio (90% CI)	AUC ratio (90% CI)			Cmax ratio (90% CI)
Mild renal impairment (creatinine clearance 51–80 mL/min)	Single olaparib tablet 300 mg dose using matched observed patient demographics and matched renal clearance from patients with mild or moderate renal impairment vs. patients with normal renal impairment from study NCT0189425613	1.24 (1.06–1.47)	1.15 (1.04–1.27)	1.40 (1.39–1.40)	1.04 (1.03–1.04)
Moderate renal impairment (creatinine clearance 31–50 mL/min)		1.44 (1.10‐1.89)	1.38 (1.06‐1.48)	1.89 (1.89–1.90)			1.09 (1.07–1.10)
Severe renal impairment and endstage renal disease (creatinine clearance ≤ 30 mL/min)		—	—	2.21 (2.19–2.22)			1.11 (1.10–1.12)
Mild hepatic impairmenta (Child–Pugh A)	Single olaparib tablet 300 mg dose using matched observed patient demographics of patients with mild or moderate hepatic impairment vs. patients with normal renal impairment from study NCT0189424313	1.15 (0.77–1.72)	1.12 (0.82–1.55)	1.38 (1.27–1.50)b	1.26 (1.26–1.28)c	1.10 (1.06–1.14)b	1.06 (1.05–1.07)c
Moderate hepatic impairmenta (Child–Pugh B)		1.08 (0.66–1.74)	0.87 (0.63–1.22)	2.50 (2.49–3.19)b	1.26 (1.15–1.32)c	1.53 (1.48–1.59)b	0.78 (0.77–0.80)c
Severe hepatic impairmenta (Child–Pugh C)		—	—	3.88 (3.74–4.02)b	1.06 (1.03–1.08)c	2.23 (2.18–2.27)b	0.59 (0.58–0.59)c
Capsule formulation
Mild renal impairment (creatinine clearance 51–80 mL/min)		—	—	1.48 (1.44–1.52)			1.21 (1.19–1.24)
Moderate renal impairment (creatinine clearance 31–50 mL/min)		—	—	1.95 (1.92–1.98)			1.28 (1.26–1.31)
Severe renal impairment and end‐stage renal disease (creatinine clearance ≤ 30 mL/min)		—	—	2.27 (2.25–2.29)			1.31 (1.28–1.33)
Mild hepatic impairmenta (Child–Pugh A)		—	—	0.95 (0.94–0.97)c			1.16 (1.15–1.16)c
Moderate hepatic impairmenta (Child–Pugh B)		—	—	1.54 (1.52–1.56)c			1.27 (1.26–1.28)c
Severe hepatic impairmenta (Child–Pugh C)		—	—	2.20 (2.13–2.28)c			1.04 (1.03–1.06)c

^aModified PBPK model with fa reduced by 34% and minimal PBPK, assuming normal GFR for predicted simulations.

^bFull/ADAM PBPK model.

^cMinimal/FO PBPK model.

^dGLS mean ratio. ADAM, advanced dissolution, absorption and metabolism; fa, fraction of absorption; FO, first order absorption; GFR, glomerular filtration rate; IC₅₀, 50% inhibitory concentration.