What to do about missing dosage history?

Background: An inaccurate or missing dose history (MDH) is one of the major obstacles in determining unbiased estimates of the pharmacokinetic (PK) parameters of a drug in clinical practice.  This is particularly the case with drug overdose when the patient may either not recall the events or choose not to provide an accurate history. Methods have been proposed to deal with MDH1,2.

Aim: The aim of the study is to develop and assess methods to accurately determine the population PK of a drug in the absence of an accurate dose history.

Methods: A hypothetical drug is assumed. The defined daily dose of the drug is Dp (100 units) once daily orally ( =24h) at prescribed time (Tp). At steady state, the patient can ingest an overdose (Do) many times bigger than Dp (1, 5, 10 and 20 times Dp)The time of overdose (To) can be anytime after the last dose. In this case the time of overdose was considered at ¼, ½, ¾ and 1 times Tp. Population PK data from a 1-compartment model with first-order elimination and absorption described by PK parameters clearance, volume of distribution and absorption rate constant were simulated. A total of 32 case scenarios are studied using a factorial design which differed at three levels, i.e. formulation (immediate release [IR] and extended release [XR]), dose level (Dp) and dosing time (Tp). Precision of several PK analysis methods – extrapolation subtraction method (ESM) [1,2], and two new methods concentration minimum method (CMM) and concentration time method (CTM) are considered.  In all of these cases the prior dose history is only considered to the level of the nominal dose and dose interval.  The actual dose and dose interval are not assumed.  These are compared to the ideal dose method (IDM), which uses the actual (simulated) dose history.

Results: The CTM is the most precise method in all the cases. The ESM performs equally well with IR formulations (i.e. when the absorption process is essentially complete before Tp). The precision of CMM improves as the value of Toapproaches Tp.

Conclusion: An accurate estimation of population PK of a drug in clinical practice is possible in the presence of inaccurate or incomplete dosing history.


1. Lena E. Friberg, G.K.I., L. Peter Hackett, Stephen B. Duffull. The Population Pharmacokinetics of Citalopram After Deliberate Self-Poisoning: A Bayesian Approach. Journal of Pharmacokinetics and Pharmacodynamics 32, 571-605 (2005).

2. Soy, D., Beal, S.L. & Sheiner, L.B. Population one-compartment pharmacokinetic analysis with  missing dosage data. Clin Pharmacol Ther 76, 441-51 (2004).