K Ogungbenro(1), H Pertinez(1) and Leon Aarons(2)
(1)Centre for Applied Pharmacokinetic Research, (2)School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
Objectives: Following PO administration, double-peaked drug concentration-time profiles in plasma can be explained by a number of different mechanisms: delayed gastric emptying; variable absorption; enterohepatic recirculation; drug secretion etc [1, 2]. Such profiles may be inadequately described by classical compartmental models and other empirical modelling approaches can used instead [1, 3, 4]. Levodopa (LDOPA, a key drug in the treatment of Parkinson’s disease) demonstrates double peak profiles attributed to its effect on gastric emptying. The main objective of this work was to propose a new semi-mechanistic model for analysing LDOPA PK data taking into account effects on gastric emptying.
Methods: Data from a simultaneous scintigraphy and paracetamol absorption test with and without LDOPA was obtained from the literature [5]. Gastric emptying profiles obtained by scintigraphy in the absence of LDOPA showed constant decline. In the presence of LDOPA, emptying is interrupted for a period associated with double peaks in both the paracetamol and LDOPA PK profiles. A semi-mechanistic emptying model, with compartments for stomach, small intestine, central and peripheral compartments, was developed to describe LDOPA PK and the double peak. A feedback mechanism acting via an effect compartment links the plasma concentration of LDOPA to the rate of gastric emptying, allowing LDOPA PK to vary the rate of gastric emptying and give rise to a multiple peaked plasma PK profile.
Results: The semi-mechanistic model was applied to plasma LDOPA and paracetemol PK data with and without simultaneous analysis of scintigraphy data, in both cases giving a good fit and in the absence of scintigraphy data adequately predicting the stomach profile. The 1st order constant governing gastric emptying was shown to switch between fast and slow values at an effect compartment concentration of ~1mg/L.
Conclusions: The new semi-mechanistic model has been used to describe the double peaks observed in the plasma concentration of LDOPA due to changes in rate of gastric emptying.
References:
[1] Godfrey KR, Arundel PA, Dong Z, Bryant R (2011) Modelling the Double Peak Phenomenon in pharmacokinetics. Comput Methods Programs Biomed 104: 62-69.
[2] Davies NM, Takemoto JK, Brocks DR, Yanez JA (2010) Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet 49: 351-377.
[3] Yin OQ, Tomlinson B, Chow AH, Chow MS (2003) A modified two-portion absorption model to describe double-peak absorption profiles of ranitidine. Clin Pharmacokinet 42: 179-192.
[4] Mirfazaelian A, Mahmoudian M (2006) A simple pharmacokinetics subroutine for modeling double peak phenomenon. Biopharm Drug Dispos 27: 119-124.
[5] Robertson DRC, Renwick AG, Wood ND, Cross N, Macklin BS, Fleming JS, Waller DG, George CF (1990) The Influence of Levodopa on Gastric-Emptying in Man. Br J Clin Pharmacol 29: 47-53.
Reference: PAGE 21 (2012) Abstr 2419 [www.page-meeting.org/?abstract=2419]
Poster: New Modelling Approaches