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
|