Table 2.
Mean AUC and Cmax ratios and model‐driven olaparib tablet or capsule dose optimization determined* from PBPK model simulations investigating the effect of CYP3A inhibitors and inducers on the exposure of olaparib tablet and capsule, and of olaparib tablet and capsule on the exposure of the CYP3A probe substrates midazolam and simvastatin, the P‐gp substrate digoxin, and the UGT1A1 substrate raltegravir
| Olaparib as a victim | ||||||
|---|---|---|---|---|---|---|
| Olaparib formulation and dose | CYP3A inhibitor/inducers schedule and dose | Parameters from observed data21 | Parameters from simulation | Olaparib prescribing information5, 6 | ||
| AUC ratio (95% CI) | Cmax ratio (95% CI) | AUC ratio (95% CI) | Cmax ratio (95% CI) | |||
| CYP3A inhibitors | ||||||
| Tablet, 100 mg single dose given 96 hours after initial itraconazole dose | Itraconazole, 0 mg vs. itraconazole, 200 mg qd for 7 days | 2.7(2.44–2.97) | 1.42(1.33–1.52) | 3.55(3.46–3.65) | 1.20 (1.2–1.21) | Reduce olaparib dose to 100 mg bid |
| Capsule, 100 mg single dose given 96 hours after initial itraconazole dose | Itraconazole, 0 mg vs. itraconazole, 200 mg qd for 7 days | — | — | 2.52 (2.39–2.67) | 1.33 (1.30–1.37) | Reduce olaparib dose to 150 mg bid |
| Tablet, 100 mg single dose given 96 hours after initial fluconazole dose | Fluconazole, 0 mg vs. fluconazole, 200 mg qd for 7 days | — | — | 2.21 (2.14–2.28) | 1.14 (1.13–1.16) | Reduce olaparib dose to 150 mg bid |
| Capsule, 100 mg single dose given 96 hours after initial fluconazole dose | Fluconazole, 0 mg vs. fluconazole, 200 mg qd for 7 days | — | — | 1.98 (1.92–2.05) | 1.17 (1.15–1.19) | Reduce olaparib dose to 200 mg bid |
| Tablet, 100 mg single dose given 96 hours after initial fluvoxamine dose | Fluvoxamine, 0 mg vs. fluvoxamine, 50 mg qd for 7 days | — | — | 1.02 (1.01–1.02) | 1.01 (1.01–1.01) | Permitted with olaparib |
| Capsule, 100 mg single dose given 96 hours after initial fluvoxamine dose | Fluvoxamine, 0 mg vs. fluvoxamine, 50 mg qd for 7 days | — | — | 1.01 (1.01–1.01) | 1.01 (1.01–1.01) | Permitted with olaparib |
| CYP3A inducers | ||||||
| Tablet, 300 mg single dose given 216 hours after initial rifampicin dose | Rifampicin, 0 mg vs. rifampicin, 600 mg qd for 13 days | 0.13 (0.11–0.16) | 0.29 (0.24–0.33) | 0.25 (0.24–0.27) | 0.56 (0.54–0.58) | Not recommended |
| Capsule, 300 mg single dose given 216 hours after initial rifampicin dose | Rifampicin, 0 mg vs. rifampicin, 600 mg qd for 13 days | — | — | 0.29 (0.27–0.31) | 0.55 (0.52–0.58) | Not recommended |
| Tablet, 300 mg single dose given 216 hours after initial efavirenz dose | Efavirenz, 0 mg vs. efavirenz, 600 mg qd for 13 days | — | — | 0.40 (0.38–0.43) | 0.69 (0.66–0.71) | Not recommended |
| Capsule, 400 mg single dose given 216 hours after initial efavirenz dose | Efavirenz, 0 mg vs. efavirenz, 600 mg qd for 13 days | — | — | 0.47 (0.44–0.50) | 0.66 (0.63–0.69) | Not recommended |
| Tablet, 300 mg single dose given 216 hours after initial dexamethasone dose | Dexamethasone, 0 mg vs. dexamethasone, 8 mg qd for 13 days | — | — | 1.00 (0.99–1.00) | 1.00 (1.00–1.00) | Permitted with olaparib |
| Capsule, 400 mg single dose given 216 hours after initial dexamethasone dose | — | — | 1.00 (0.99–1.00) | 1.00 (1.00–1.00) | Permitted with olaparib | |
| Olaparib as a perpetrator | ||||||
| Probe substrate and dose | Olaparib formulation, schedule and dose | Substrate parameters from simulation | Dosing recommendations | |
|---|---|---|---|---|
| AUC ratio (95% CI) | Cmax ratio (95% CI) | |||
| Midazolam 5 mg single dose given 96 hours after initial olaparib dose | Tablet, 0 mg vs. tablet, 300 mg bid for 7 days | 1.61 (1.42–1.83) | 1.18 (1.10–1.27) | EMA: Caution should be exercised when substrates which are sensitive or with a narrow therapeutic margin are combined with olaparib FDA: None stated |
| Capsule, 0 mg vs. capsule, 400 mg bid for 7 days | 1.45 (1.27–1.65) | 1.11 (1.04–1.19) | EMA: Caution should be exercised when sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic margin are combined with olaparib FDA: None stated | |
| Simvastatin 40 mg single dose given 96 hours after initial olaparib dose | Tablet, 0 mg vs. tablet, 300 mg bid for 7 days | 1.54 (1.33–1.78) | 1.33 (1.18–1.49) | EMA: Caution should be exercised when substrates which are sensitive or with a narrow therapeutic margin are combined with olaparib FDA: None stated |
| Capsule, 0 mg vs. capsule, 400 mg bid for 7 days | 1.47 (1.27–1.71) | 1.27 (1.13–1.43) | EMA: Caution should be exercised when sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic margin are combined with olaparib FDA: None stated | |
| Digoxin 0.5 mg (0.25 mg in capsule study) single dose given 96 hours after initial olaparib dose | Tablet, 0 mg vs. tablet, 300 mg bid for 7 days | 1.02 (1.02–1.02) | 1.05 (1.04–1.05) |
In vitro, olaparib inhibits the efflux transporter P‐gp (IC50 = 76 μM), therefore it cannot be excluded that olaparib may cause clinically relevant drug interactions with substrates of P‐gp (e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medicinal product concomitantly. FDA: None stated |
| Capsule, 0 mg vs. capsule, 400 mg bid for 7 days | 1.02 (1.02–1.02) | 1.03 (1.03–1.03) |
EMA: In vitro, olaparib inhibits the efflux transporter P‐gp (IC50 = 76 μM), therefore it cannot be excluded that olaparib may cause clinically relevant drug interactions with substrates of P‐gp (e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medicinal product concomitantly. FDA: None stated |
|
| Raltegravir 400 mg single dose given 96 hours after initial olaparib dose | Tablet, 0 mg vs. tablet, 300 mg bid for 8 days | 1.07 (1.06–1.08) | 1.04 (1.04–1.04) | EMA: Olaparib inhibited UGT1A1 in vitro, however, PBPK simulations suggest this is not of clinical importance. FDA: None stated |
| Capsule, 0 mg vs. capsule, 400 mg bid for 7 days | 1.04 (1.03–1.05) | 1.02 (1.01–1.03) | Olaparib inhibited UGT1A1 in vitro, however, PBPK simulations suggest this is not of clinical importance | |
Study simulation parameters required for dose adjustment recommendation: the simulated olaparib/CYP3A modulator exposure as monotherapy should be <2‐fold that of the coadministered combination. Data are expressed as geometric mean. qd, once daily.