Table 2.
Parameter values used for the cyclosporine simulations
| Parameter | Value | Reference/comments |
|---|---|---|
| Molecular weight (g/mol) | 1,202 | |
| fu—experimental | 0.0365 | [60] |
| Blood/plasma ratio (B:P)—experimental | 1.36 | [31] |
| Log of the octanol:water partition coefficient (logP o:w)—experimental | 2.96 | [61, 62] |
| Compound type | Neutral | |
| Main plasma binding protein | HSA (human serum albumin) | |
| Absorption | ||
| Model | ADAM | |
| Effective permeability (P eff,man) (10−4 cm/s) | 1.65 | [63] |
| Effective colonic permeability (P eff,man,colon) (10−4 cm/s) | 0.001 | Permeability in the colon was set to ~0 in order to achieve an fa of <1 (consistent with observed data) |
| fa—predicted | 0.857 | Based on observed P eff,man |
| k a (h−1)—predicted | 0.679 | Based on observed P eff,man |
| k a (h−1)—observed | 0.68–1.6 | Range [64, 65] |
| Distribution | ||
| Model | Full PBPK | Rodgers and Rowland method; see text for details |
| V ss (L/kg)—predicted | 1.7 | When applying K p liver and K p spleen |
| V ss (L/kg)—observed | 1.48 | [64, 66] |
| Liver partition coefficient (K p) | 11 | [67] |
| Spleen partition coefficient (K p) | 7.7 | [67] |
| Elimination | ||
| CLiv (L/h) | 24.07 | [64, 66] |
| Intrinsic clearance (CLint CYP3A4) (μL/min/pmol CYP) | 2.64 | Calculated using the retrograde approach |
| CLR (L/h) | 0.024 | Applying fe (fraction of drug excreted) of 0.001 (Sandimmune Prescribing Information) to a systemic clearance of 24.07 L/h |
| Interaction | ||
| K i—intestinal BCRP (μmol/L) | 0.28 | See text for details; [56, 57] |
| K i—hepatic OATP1B1 (μmol/L) | 0.014 | [56, 57] |
| K i—hepatic OATP1B3 (μmol/L) | 0.007 | See text for details; [56, 57] |
| K i—hepatic NTCP (μmol/L) | 0.63 | See text for details [56, 57] |
| K i—hepatic BCRP (μmol/L) | 0.28 | See text for details [56, 57] |
ADAM Advanced Dissolution, Absorption and Metabolism, BCRP breast cancer resistance protein, CL iv in vivo systematic clearance, CL R renal clearance, CYP cytochrome P450, fa fraction absorbed, fu fraction unbound in plasma, k a absorption rate constant, K i concentration of inhibitor that supports half-maximal inhibition, K p tissue-to-plasma partition coefficient, NTCP sodium-dependent taurocholate co-transporting polypeptide, OATP organic anion-transporting peptide, PBPK physiologically based pharmacokinetic, V ss volume of distribution at steady state