Simulated vs. Observed Theophylline Absorption PK at 1 Week Following Daily Administration of a Sustained Release Formulation in Older Children (8-14 yrs)
| Source | Mean Cmax [mcg/mL] (CV%a) | Mean Cmin [mcg/mL] (CV%) | Mean Percent Fluctuation (%)b (CV%) | |||
|---|---|---|---|---|---|---|
| ic | iid | i | ii | i | ii | |
| Observed | ||||||
| Pedersen and Steffensen, 1987 | 12.86 | 12.18 | 6.79 | 7.29 | 95.78 | 72.80 |
| (24.84%) | (26.07%) | (33.03%) | (31.69%) | (26.77%) | (40.34%) | |
| Simulated-PBPK | ||||||
| SITT (adult) | 12.53e | 8.48 | 52.39 | |||
| LITT (adult) | (27.15%) | (37.68%) | (25.60%) | |||
| SITT (↓ 25%)f | 12.53 | 8.48 | 52.38 | |||
| LITT (adult) | (27.16%) | (37.68%) | (25.63%) | |||
| SITT (↓ 50%) | 12.53 | 8.48 | 52.38 | |||
| LITT (adult) | (27.15%) | (37.68%) | (25.63%) | |||
| SITT (↓ 25%) | 12.53 | 8.48 | 52.40 | |||
| LITT (↓ 25%)g | (27.14%) | (37.68%) | (25.65%) | |||
| SITT (↓ 50%) | 11.15 | 7.81 | 46.91 | |||
| LITT (↓ 50%) | (29.01%) | (38.66%) | (24.49%) | |||
↵a coefficient of variation;
↵b percent fluctuation between peak and trough plasma concentration values over a given dosing interval (i.e. [peak – trough]/trough);
↵c Data reported by Pedersen and Steffensen on Day 6 following oral maintenance (q24h) therapy with a sustained release theophylline formulation (Noctelin – Riker Labs Inc, Loughborough, UK) [n = 14];
↵d Data reported for 10 of 14 children investigated by Pedersen and Steffensen on Day 7 following oral maintenance (q24h) therapy with a sustained release theophylline formulation (Noctelin – Riker Labs) [n = 10 – same study group as depicted above; data for 4 children was unavailable];
↵e PBPK models were not parameterized to include intradose variability. (i.e. once steady-state was achieved, concentration-time values were congruent between dosing intervals). As such, simulated data is only provided as a single value obtained on day 7 of theophylline maintenance dosing [n = 50];
↵f 25% reduction in small intestinal transit time (SITT) from adult values. SITT for normal adults was parameterized as 2.1h - the default PK-Sim® v5.2 value. This represent the time span between gastric emptying of 63% of a nonabsorbable marker and localization of 90% of the marker within the caecum.
↵g 25% reduction in large intestinal transit time (LITT) from adult values. LITT for normal adults was parameterized as 44.2h - the default PK-Sim® v5.2 value. This represent the time span between 90% of a nonabsorbable marker reaching the caecum and localization of 70% of the marker within the feces;