Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes

FIGURE 1. Schematic structure of whole PBPK-PD model of CLOP. Where, gw, ROB, Q and Q total were gut wall compartment, rest of body compartment, blood flow rates and cardiac output. K t,i, K a, and K b represent the gastrointestinal transit rate constants, drug absorption rate constant and drug efflux rate constant, respectively. CL int,CYP450 and CL int,CES1 represent the CYP450 and CES1-mediated intrinsic clearances respectively. k irre, k in, and k out were CLOP-AM-mediated irreversible antiplatelet aggregation rate constant, platelet aggregation rate constant and platelet disaggregation rate constant, respectively.

FIGURE 2. The predicted (line) and observed (point) plasma concentration-time profiles in healthy volunteers. (A) CLOP concentrations after 300 mg single dose. The observations were from Kim (2014, EM n = 7, IM n = 8, PM n = 7) (Kim et al., 2014) and Song (EM n = 8, IM n = 10, PM n = 2) (Song et al., 2018). (B) CLOP-AM concentrations after 300 mg single dose; (C) CLOP-AM after 300 mg loading dose followed by 75 mg maintenance dose on d7. The observations were cited came from Kobayashi (EM n = 9, IM n = 9, PM n = 9) (Kobayashi et al., 2015), Song (EM n = 8, IM n = 10, PM n = 2) (Song et al., 2018), Umemura (EM n = 8, IM n = 21, PM n = 7) (Umemura and Iwaki, 2016) and Zhang (EM n = 16, IM n = 16, PM n = 16) (Zhang et al., 2020). (D) CLOP-AM concentrations after 600 mg single dose; and (E) CLOP-AM after 600 mg loading dose followed by 150 mg maintenance dose on d7. The observed data were from Kobayashi (EM n = 9, IM n = 9, PM n = 9) (Kobayashi et al., 2015). (F) The relationship between the observed and predicted plasma concentrations of CLOP/CLOP-AM in healthy individuals. Solid and dashed lines respectively represent unity and 2-fold errors between observed and predicted data.

FIGURE 3. The predicted (line) and observed (point) IPA-time profiles in healthy volunteers. (A) IPA (%) after 300 mg single dose. The observations were cited from Kim (2008, EM n = 8, IM n = 8, PM n = 8) (Kim et al., 2008), Kim (2016, EM n = 9, IM n = 9, PM n = 9) (Kim et al., 2016), Kobayashi (EM n = 9, IM n = 9, PM n = 9) (Kobayashi et al., 2015), Simon (UM n = 10, EM n = 10, IM n = 10, PM n = 10) (Simon et al., 2011), Song (EM n = 8, IM n = 10, PM n = 2) (Song et al., 2018), Tazaki (EM n = 13, IM n = 10, PM n = 4) (Tazaki et al., 2012), Umemura (EM n = 8, IM n = 21, PM n = 7) (Umemura and Iwaki, 2016) and Zhang (EM n = 16, IM n = 16, PM n = 16) (Zhang et al., 2020). (B) IPA (%) after 600 mg single dose, whose observed data were from Kobayashi (EM n = 9, IM n = 9, PM n = 9) (Kobayashi et al., 2015) and Simon (UM n = 10, EM n = 10, IM n = 10, PM n = 10) (Simon et al., 2011). (C) IPA(%) after multidose of 75 mg, whose observations were from Horenstein (EM n = 6, IM n = 6, PM n = 6) (Horenstein et al., 2014), Kelly (EM n = 34, IM n = 38, PM n = 11) (Kelly et al., 2012) and Nakkam (EM n = 13, IM n = 18, PM n = 4) (Nakkam et al., 2015). (D) IPA (%) after 300 mg loading dose followed by 75 mg…

FIGURE 4. The predicted (line) and observed (point) plasma concentration-time profiles and IPA-time profiles following oral dose to CAD patients carrying different CYP2C19 phenotypes. (A) CLOP after 75 mg maintenance dose daily, and the observed data were from Danielak (UM n = 25, EM n = 18, IM n = 20) (Danielak et al., 2017), Fallah (EM n = 5) (Fallah et al., 2016) and Karazniewicz-Lada (UM n = 18, EM n = 16, IM n = 10) (Karazniewicz-Lada et al., 2014); (B) CLOP-AM after 75 mg maintenance dose daily, and the observed data were from Danielak (UM n = 25, EM n = 18, IM n = 20) (Danielak et al., 2017) and Karazniewicz-Lada (UM n = 18, EM n = 16, IM n = 10) (Karazniewicz-Lada et al., 2014). (C) shows the relationship between the observed and predicted plasma concentration of CLOP and CLOP-AM in different metabolizers. Solid and dashed lines respectively represent unity and 2-fold errors between observed and predicted data. (D) IPA (%) after 75 mg maintenance dose daily without loading dose, the observed data were from Erlinge (EM n = 49, PM n = 14) (Erlinge et al., 2014), Gurbel (2013, EM n = 36, PM n = 10 for smokers; EM n = 45, PM n = 9 for nonsmokers) (Gurbel et al., 2013) and Gurbel (2014,…

FIGURE 5. The predicted and observed pharmacokinetic and pharmacodynamic profiles in CAD patients with DM. Plasma concentration-time (A) profile and IPA (B) of CLOP-AM after 600 mg single dose to CAD patients with DM (without considering CYP2C19 phenotypes). The observations from Angiolillo (2011, n = 34) (Angiolillo et al., 2011a), Angiolillo (2014, n = 30) (Angiolillo et al., 2014), Clavijo (n = 21) (Clavijo et al., 2015) and Sweeny (n = 16) (Sweeny et al., 2017). The simulated plasma concentrations (C) of CLOP-AM and (D) IPA (%)-time profile after 300 mg loading dose followed by 75 mg maintenance dose to CAD patient with DM carrying CYP2C19 phenotypes. The observations from Carreras (EM n = 82, PM n = 27) (Carreras et al., 2016), Liu (no data) (Liu et al., 2014), Oestreich (UM n = 14, EM n = 62, IM n = 22) (Oestreich et al., 2014). (E) simulated dose- and CYP2C19 phenotype-dependent IPA following 300 mg loading dose followed by maintenance dose in CAD patients with DM, CAD-EMs without DM served as control.

FIGURE 6. Results of visual predictive checks. Visual predictive checks of the predicted concentrations of CLOP-AM and IPA following 300 mg oral single dose of CLOP (A,B) or loading dose 300 mg followed by75 mg maintenance dose (C,D) of CLOP to healthy individuals. The observations were cited from Horenstein (EM n = 6, IM n = 6, PM n = 6) (Horenstein et al., 2014), Kelly (EM n = 34, IM n = 38, PM n = 11) (Kelly et al., 2012), Kim (2008, EM n = 8, IM n = 8, PM n = 8) (Kim et al., 2008), Kim (2014, EM n = 7, IM n = 8, PM n = 7 for pharmacokinetics; EM n = 33, IM n = 37, PM n = 32 for pharmacodynamics) (Kim et al., 2014), Kim (2016, EM n = 9, IM n = 9, PM n = 9) (Kim et al., 2016), Kobayashi (EM n = 9, IM n = 9, PM n = 9) (Kobayashi et al., 2015), Song (EM n = 8, IM n = 10, PM n = 2) (Song et al., 2018), Umemura (EM n = 8, IM n = 21, PM n = 7) (Umemura and Iwaki, 2016), Zhang (EM n = 16, IM n = 16, PM n = 16) (Zhang et al., 2020), Tazaki (EM n = 13, IM n = 10, PM n = 4) (Tazaki et al., 2012), Simon (UM n = 10, EM n = 10, IM n = 10, PM n = 10) (Simon et al., 2011) and Nakkam (EM n = 13, IM n = 18, PM n = 4) (Nakkam et al., 2015).

FIGURE 7. Results of sensitivity analysis. The effects of variations in K t,i (A), V max,CYP2C9 (B), V max,CYP2C19 (C), V max,CYP3A4 (D) and CL int,CES1 (E) on pharmacokinetic profiles of CLOP following oral 300 mg of CLOP to healthy individuals; (F) the individual contributions of alterations in V max,CYP2C19, V max,CYP3A4, CL int,CES1 and K t,i to pharmacokinetics of CLOP-AM and their integrations following oral 600 mg of CLOP to CAD patients with DM. The effects of variations in K t,i (G), activities of V max,CYP2C9 (H), V max,CYP2C19 (I), V max,CYP3A4 (J), CL int,CES1 (K) and k irre (L) on IPA(%) of CLOP-AM following oral dose of 300 mg CLOP to healthy individuals.