Article Figures & Data
Figures
- Fig. 1.
Schematic of the mPBPK/PD model for PK and effects of MPL on adrenal suppression in male and female rats. Parameters are defined in the text and in Tables 2 and 3. The model is described by eqs. 2–11.
- Fig. 2.
PK profiles of MPL (50 mg/kg IM) in (A) plasma of 7-week-old (Cohort 4) and 11-week-old (Cohort 5) male rats; (B) plasma of estrus females (Cohort 1), proestrus females (Cohort 2), noncycling (NC) females (Cohort 3), and males (Cohorts 4 and 5); (C) plasma of females (Cohorts 1–3) and males (Cohorts 4 and 5); and (D) livers of females (Cohort 2) and males (Cohort 4). Symbols depict either replicate data from each animal (A) or mean observed data ± S.D. (B–D). Symbols are defined within the figure.
- Fig. 3.
Model fittings of the concentration–time profiles of total MPL in plasma (A) and liver (B) of male and female rats that received 50 mg/kg IM doses of MPL. Symbols depict mean observed data ± S.D. Solid lines represent model-fitting results for each sex. Symbols are defined within the figure.
- Fig. 4.
Model-based simulations of the PK profiles of MPL following 10 mg/kg (dashed line) and 50 mg/kg (solid line) IV doses in normal male rats. Triangles are low-dose data obtained from Jin and Jusko (2009), whereas open circles are high-dose data taken from Hazra et al. (2007b). Parameter values used in the simulations are listed in part in Table 2.
- Fig. 5.
Model fittings of plasma CST dynamics in estrus female rats (left), proestrus female rats (middle), and male rats (right) that received 50 mg/kg IM doses of MPL. Symbols depict mean observed data ± S.D. Solid lines represent model-fitting results for each group after MPL dosing, and broken line depicts simulated profile of CST rhythm in control animals. Dark (shaded) and light (unshaded) time periods are indicated.
Tables
- TABLE 1
PK parameters using NCA for plasma MPL in the study cohorts after intramuscular administration
Experimental Group (n) λz (h−1) T1/2_λz (h) Cmax (ng/ml) AUC0-∞ (h × ng/ml)b CL/F (ml/h per kilogram) Cohort 1: estrus female (30) 0.24 2.9 5348 ± 488 10,489 ± 1054 4767 ± 479 Cohort 2: proestrus female (39) 0.27 2.6 3859 ± 777 9142 ± 646 5469 ± 386 Cohort 3: noncycler female (20) 0.20 3.4 3796 ± 188 8735 ± 601 5723 ± 394 Cohort 4: male 7 wk (31) 0.25 2.7 1470 ± 109 2808 ± 167 17,806 ± 1059 Cohort 5: male 11 wk (23) 0.26 2.6 1054 ± 94 2885 ± 312 17,334 ± 1875 All females 0.24 2.9 4204 ± 323 9751 ± 482 5128 ± 252 All males 0.28 2.5 1174 ± 194 2901 ± 185 17,232 ± 1099 CL/F, clearance; T1/2, half-life.
a Values represent mean ± S.E.
↵b AUC calculated using Bailer’s method for sparse (destructive) sampling.
Parameter Definition Estimate (% CV) F Bioavailability 0.214a Fr Fraction absorbed by ka1 0.725a ka1 (h−1) Absorption rate constant 0.8 (8.8)b/4.1 (24.8)c ka2 (h−1) Absorption rate constant 0.17 (17.3) CLEH (ml/h) Extrahepatic clearance 347 (4.2) CLu,int,male (ml/h) Hepatic unbound intrinsic clearance (male) 2987 (12.7) KP, hep Partition coefficient—liver 12.6 (7.6) KP, PPT (muscle) Partition coefficient—poorly perfused tissue 1.4d KP, RPT (lung) Partition coefficient—richly perfused tissue 2.1d fu,p MPL fraction unbound in plasma 0.4d Parameter Definition Estimate (% CV) Circadian Rhythm Parameters for CST T (h) Biorhythmic period 24a,b,c a0 Fourier coefficient 115.7a,b/254.4b a1 −120.9a,b/−168.7b a2 38.8a,b/56.9b b1 −41.1a,b/−95.6b b2 1.6a,b/29.1b Pharmacodynamic Parameters kdeg,CST (h−1) Loss rate constant for CST 1.38 (12.6)a,b,c τ (h) Time to CSTstress 0.34 (12.8)a,b,c CSTstress (ng/ml) Maximal CST due to stress 535 (18.0)a/1292 (13.3)b/1397 (12.9)c IC50,CST (ng/ml) Half-maximal inhibition concentration 3.4 (47.6)a/41.6 (48.0)b/12.9 (45.6)c
Data Supplement
- Supplemental Data -
Supplemental model.
- Supplemental Data -
In this issue
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