Table 1. Input data for the full physiologically-based pharmacokinetic (PBPK) model for buprenorphine
Parameter Parameter Parameter Value
Physiochemical Physiochemical Physiochemical
Molecular weight (g mol-1) Molecular weight (g mol-1) 467.634
LogP LogP 4.9835
Compound type Compound type Ampholyte35
pKa (acid; phenol) pKa (acid; phenol) 9.6235
pKa (base; amine) pKa (base; amine) 8.3135
Blood binding Blood binding Blood binding
B/P B/P 136
fu, plasma fu, plasma 0.0437
Plasma binding components Plasma binding components AGP38
Gastrointestinal tract absorption (first-order model) Gastrointestinal tract absorption (first-order model) Gastrointestinal tract absorption (first-order model)
fa fa 1a
ka (h-1) ka (h-1) 0.016b
Lag time (h) Lag time (h) 0.22c
fu, gut fu, gut 0.4b
Qgut (L h-1) Qgut (L h-1) 16.8d
Peff, man (10-4 cm s-1) Peff, man (10-4 cm s-1) 6.83d
Caco-2 7.4:7.4 (10-6 cm s-1) Caco-2 7.4:7.4 (10-6 cm s-1) 66.739
Lunge absorption (first-order model) Lunge absorption (first-order model) Lunge absorption (first-order model)
fa fa 1a
ka (h-1) ka (h-1) 1b
Proportion of dose inhaledetablet (%) Proportion of dose inhaledetablet (%) 38.1 – 19.7 × log(Dose)f
Proportion of dose inhaledesolution (%) Proportion of dose inhaledesolution (%) 53.3 – 25.6 × log(Dose)f
Distribution (full PBPK model) Distribution (full PBPK model) Distribution (full PBPK model)
Tissue-to-plasma partition coefficients (Kp) Tissue-to-plasma partition coefficients (Kp)
Adiposeg 17.80038
Boneh 1.60338
Brainh 19.20638
Guti 2.25238
Hearth 1.71438
Kidneyi 6.37238
Liveri 8.69538
Lungh 3.92138
Muscleh 0.90538
Pancreash 3.01638
Skin 3.50040
Spleenh 2.28638
Predicted Vss (L kg-1) Predicted Vss (L kg-1) 6.23d
Observed Vss (L kg-1) Observed Vss (L kg-1) 4.9541
Elimination Elimination Elimination
CYP2C8 CYP2C8
Vmax (pmol min-1 per mg protein) 176.342
Km (μM) 12.442
CYP3A4 CYP3A4
Vmax (pmol min-1 per mg protein) 52042
Km (μM) 13.642
UGT1A1 UGT1A1
Vmax (pmol min-1 per mg protein) 287043
Km (μM) 66.443
UGT1A3 UGT1A3
Vmax (pmol min-1 per mg protein) 28643
Km (μM) 20243
UGT2B7 UGT2B7
Vmax (pmol min-1 per mg protein) 17343
Km (μM) 13.843
UGT2B17 UGT2B17
Vmax (pmol min-1 per mg protein) 17243
Km (μM) 9.643
fu, mic fu, mic 0.144
CLrenal (L h-1) CLrenal (L h-1) 0.54j
CLbiliary (μl min-1 per million cells) CLbiliary (μl min-1 per million cells) 5133
AGP, α1-acid glycoprotein; B/P, blood-to-plasma ratio; CLbiliary, biliary clearance; CLrenal, renal clearance; CYP, cytochrome P450; fa, fraction absorbed; fu, gut, fraction unbound in enterocytes; fu, mic, fraction unbound in in vitro microsomal incubation; fu, plasma, fraction unbound in blood plasma; ka, first-order absorption rate constant; Km, Michaelis-Menten constant; Peff, man, human jejunum effective permeability; Qgut, nominal flow in gut model; UGT, UDP-glucuronosyltransferase; Vmax, maximum metabolic rate; Vss, volume of distribution at steady-state. AGP, α1-acid glycoprotein; B/P, blood-to-plasma ratio; CLbiliary, biliary clearance; CLrenal, renal clearance; CYP, cytochrome P450; fa, fraction absorbed; fu, gut, fraction unbound in enterocytes; fu, mic, fraction unbound in in vitro microsomal incubation; fu, plasma, fraction unbound in blood plasma; ka, first-order absorption rate constant; Km, Michaelis-Menten constant; Peff, man, human jejunum effective permeability; Qgut, nominal flow in gut model; UGT, UDP-glucuronosyltransferase; Vmax, maximum metabolic rate; Vss, volume of distribution at steady-state. AGP, α1-acid glycoprotein; B/P, blood-to-plasma ratio; CLbiliary, biliary clearance; CLrenal, renal clearance; CYP, cytochrome P450; fa, fraction absorbed; fu, gut, fraction unbound in enterocytes; fu, mic, fraction unbound in in vitro microsomal incubation; fu, plasma, fraction unbound in blood plasma; ka, first-order absorption rate constant; Km, Michaelis-Menten constant; Peff, man, human jejunum effective permeability; Qgut, nominal flow in gut model; UGT, UDP-glucuronosyltransferase; Vmax, maximum metabolic rate; Vss, volume of distribution at steady-state. AGP, α1-acid glycoprotein; B/P, blood-to-plasma ratio; CLbiliary, biliary clearance; CLrenal, renal clearance; CYP, cytochrome P450; fa, fraction absorbed; fu, gut, fraction unbound in enterocytes; fu, mic, fraction unbound in in vitro microsomal incubation; fu, plasma, fraction unbound in blood plasma; ka, first-order absorption rate constant; Km, Michaelis-Menten constant; Peff, man, human jejunum effective permeability; Qgut, nominal flow in gut model; UGT, UDP-glucuronosyltransferase; Vmax, maximum metabolic rate; Vss, volume of distribution at steady-state.
aAssumed value. bOptimized using the concentration-time profile for the sublingual tablet dose of 24 mg reported by Dong et al.28 cAverage of lag times obtained through Bayesian estimation by fitting the buprenorphine population pharmacokinetic (PK) model reported by Moore et al.46 to the concentration-time profiles reported by Dong et al.28 (doses ranging from 2 to 24 mg as sublingual tablets). dSimcyp predicted value. eThe sublingual route of administration is not available in Simcyp; sublingual absorption is therefore mimicked by employing the first-order inhalation model in combination with the inhaled route of administration. fDose is in mg and logarithm base is 10. The value is calculated manually and the computed proportion is then entered into the first-order inhalation model. Note that a coefficient of variation (CV) of 33.9% is applied to the administered dose to reflect variability in bioavailability; more details are provided in this manuscript. g,h,iReported radioactivity at 24, 8, and 1 h post-injection was used for calculation, respectively. jCalculated by Johnson et al.33 based on a mass balance study where 1% was excreted unchanged in urine,45 with total plasma clearance of 54.1 L/h.36 aAssumed value. bOptimized using the concentration-time profile for the sublingual tablet dose of 24 mg reported by Dong et al.28 cAverage of lag times obtained through Bayesian estimation by fitting the buprenorphine population pharmacokinetic (PK) model reported by Moore et al.46 to the concentration-time profiles reported by Dong et al.28 (doses ranging from 2 to 24 mg as sublingual tablets). dSimcyp predicted value. eThe sublingual route of administration is not available in Simcyp; sublingual absorption is therefore mimicked by employing the first-order inhalation model in combination with the inhaled route of administration. fDose is in mg and logarithm base is 10. The value is calculated manually and the computed proportion is then entered into the first-order inhalation model. Note that a coefficient of variation (CV) of 33.9% is applied to the administered dose to reflect variability in bioavailability; more details are provided in this manuscript. g,h,iReported radioactivity at 24, 8, and 1 h post-injection was used for calculation, respectively. jCalculated by Johnson et al.33 based on a mass balance study where 1% was excreted unchanged in urine,45 with total plasma clearance of 54.1 L/h.36 aAssumed value. bOptimized using the concentration-time profile for the sublingual tablet dose of 24 mg reported by Dong et al.28 cAverage of lag times obtained through Bayesian estimation by fitting the buprenorphine population pharmacokinetic (PK) model reported by Moore et al.46 to the concentration-time profiles reported by Dong et al.28 (doses ranging from 2 to 24 mg as sublingual tablets). dSimcyp predicted value. eThe sublingual route of administration is not available in Simcyp; sublingual absorption is therefore mimicked by employing the first-order inhalation model in combination with the inhaled route of administration. fDose is in mg and logarithm base is 10. The value is calculated manually and the computed proportion is then entered into the first-order inhalation model. Note that a coefficient of variation (CV) of 33.9% is applied to the administered dose to reflect variability in bioavailability; more details are provided in this manuscript. g,h,iReported radioactivity at 24, 8, and 1 h post-injection was used for calculation, respectively. jCalculated by Johnson et al.33 based on a mass balance study where 1% was excreted unchanged in urine,45 with total plasma clearance of 54.1 L/h.36 aAssumed value. bOptimized using the concentration-time profile for the sublingual tablet dose of 24 mg reported by Dong et al.28 cAverage of lag times obtained through Bayesian estimation by fitting the buprenorphine population pharmacokinetic (PK) model reported by Moore et al.46 to the concentration-time profiles reported by Dong et al.28 (doses ranging from 2 to 24 mg as sublingual tablets). dSimcyp predicted value. eThe sublingual route of administration is not available in Simcyp; sublingual absorption is therefore mimicked by employing the first-order inhalation model in combination with the inhaled route of administration. fDose is in mg and logarithm base is 10. The value is calculated manually and the computed proportion is then entered into the first-order inhalation model. Note that a coefficient of variation (CV) of 33.9% is applied to the administered dose to reflect variability in bioavailability; more details are provided in this manuscript. g,h,iReported radioactivity at 24, 8, and 1 h post-injection was used for calculation, respectively. jCalculated by Johnson et al.33 based on a mass balance study where 1% was excreted unchanged in urine,45 with total plasma clearance of 54.1 L/h.36