Subjective variability

Is the within- or between-subject variability acceptable given the likely therapeutic index of the compound ... 

If there is a very large within- or between-subject variability in apparent clearance this might indicate variable absorption or bioavailability, which in turn is often seen when absorption or bioavailability is low. 

Subject variability High intraindividual variability in QTc values (circadian and seasonal variation law of regression to the mean) High interindividual variability in QTc values (males versus females) Unknown prevalence in the general population of subjects carrying silent mutations in the ion channels responsible for cardiac repolarization (these subjects have normal QTc value but reduced repolarization reserve) Variability in the individual metabolic capacity for a given drug... 

Talbot RJ, Newton D, Priest ND, et al. 1995. Inter-subject variability in the metabolism of aluminum following intravenous injection as citrate. Hum Exp Toxicol 14 595-599. 

Fig. 12.4 Pharmacokinetic-pharmacodynamic model ofthethrombopoietic effects of a thrombopoietin analogue (PEG-rHuMGDF) in healthy volunteers. The intrinsic longevity of platelets (A), nonlinear random destruction of platelets (p), and the intra-subject variability...

BSA (p <0.0001). The least-squares mean clearance for a patient with a BSA of 1.83 m2 at 2.3 mg/m2 was 62 L/h, but was 30 L/h at 62.2 mg/m2. Decreasing clearance with increasing dose is consistent with Michaelis-Menten elimination kinetics. Between-subject variability was moderate at approximately 30%. Tasidotin did not show any major renal elimination, with only ca. 13% of the dose being found in the urine as unchanged drug. In Study 103, the least-squares mean tasidotin renal clearance was approximately 4.3 L/h (about 13% of total systemic clearance), with a between-subject variability of approximately 51%. Given a glo-... 

The least-squares mean tasidotin total volume of distribution at steady state was 10 L, and was not affected by dose or day of administration. Between-subject variability was estimated at 39%. The tasidotin half-life did not change over day of administration, but increased with increasing dose (p < 0.0001) and decreased with increasing BSA (p = 0.0144). The least squares mean half-life was 26 min at 2.3 mg/m2, but was 46 min at 62.2 mg/m2. Between-subject variability was estimated at approximately 20%. The finding that the half-life was dose-dependent was not surprising, as total systemic clearance was affected by both dose and BSA, whereas volume of distribution at steady state was unaffected by dose or BSA. Under these conditions, the half-life would be expected to change inversely proportional to clearance. 

Dose proportionality was assessed using the power model. AUC0 24 and Cmax did not change over day of administration, but did increase with increasing dose (p <0.0001 see Fig. 13.3). For AUC0 24, the 90% Cl for the slope related to dose was 0.96, 1.18 with a point estimate of 1.07. The 90% Cl for the slope related to Cmax was 1-02, with a 90% Cl of 0.92, 1.13. Hence, the 90% Cl for both AUC0 24 and Cmax contained the value 1.0 and both parameters were dose-proportional. The between-subject variability for AUC0 24 and Cmax was 32% and 40%, respectively. 

Most subjects provided insufficient data to estimate the half-life of the carboxy-late metabolite. Nevertheless, sufficient data were available from 14 patients, from which an estimate of ILX651-C-carboxylate half-life could be determined. Neither day of administration, BSA, nor dose had any influence on ILX651-C-carboxylate half-life. The least-squares mean ILX651-C-carboxylate half-life was 8 h, which was considerably longer than the half-life of tasidotin. Between-subject variability in metabolite half-life was 17%. Given a parent half-life of less than 1 h, metabolite concentrations were not formation rate-limited. Given the half-life of the metabolite, little accumulation of the metabolite would be expected. 

Ward SA, Watkins WM, Mberu E, et al. Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man. Br J Clin Pharmacol 1989 27 781-787. 

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