Population pharmacokinetic modelling of sustained-release lithium in the serum, erythrocytes and urine of patients with bipolar disorder.
C. Couffignal(1,2,3), J. Bertrand(2,3), S. Sportiche(4,5,6), Marine Jarroir(4,5,6), X. Declèves(4,5,6), F. Mentré(1,2,3) and F. Bellivier(4,5,6)
(1) AP-HP, HUPNVS, Paris, France (2) Univ Paris Diderot, IAME, UMR1137, Sorbonne Paris Cité, Paris, France (3) INSERM, IAME, UMR 1137, Paris, France (4) AP-HP, Hop Fernand Widal- Lariboissière, Paris, France (5) Univ Paris Descartes, VariaPsy, UMR 1144, Sorbonne Paris Cité, Paris, France (6) INSERM, VariaPsy, UMR 1144, Paris, France
Objectives: Bipolar disorder is a major affective disorder. Sustained-release lithium (srLI) is now the first-line treatment with a narrow therapeutic margin adapted empirically from immediate-release form studies [1]. Indeed, to date, there exist no specific pharmacokinetics (PK) studies for the sustained-release form. Our aim was to propose a population model of the PK of srLI using serum (S), erythrocyte (E) and urinary (U) samples in bipolar patients.
Methods: A prospective study was conducted in French bipolar disorder centers in patients treated with srLI for at least two years. For 15 days srLI was given once per day in the morning at the patient usual dose. Adherence was controlled using a medication event monitoring system [2]. Blood samples were collected at day 15 before drug intake and at H1, H4, and H8, with U samples between H0 and H8. Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software) [3].
Results: Seventeen patients were included from, age median=40 range [27-63] y and srLI dose 1000 [600-1600] mg. The srLI PK was best described with an 8 parameters model with a first order absorption process with bioavailability F and a lag-time Tlag, a S one-compartment with an elimination clearance Cls to the U one-compartment, a E one-compartment with a transfer clearance Clse into the E compartment and a transfer clearance Cles back to the S compartment. A proportional variance model best described the residual errors for the S concentrations. For the E concentrations and U amount the residual errors were best depicted by an additive variance model. The mean and between-subject variability (BSV %, if estimated) were for F= 62% (98%), Tlag=55 minutes and ka=2.22 h-1 (72%), Vs=23 L (30%), Cls=1.21 L.h-1 (20%) and Clse=3.63 L.h-1, Ve=64.7 L, Cles=9.46 L.h-1 (27%). The goodness-of-fit plots were satisfactory. The ratio of exposition to LI in E over S (as measured by the ratio of predicted AUCss) is of 0.38 (20%).
Conclusions: This is the first study in bipolar patients to inform on srLI PK and provide mean and BSV estimates of the ratio of exposition to LI in E over S which is deemed to be a proxy of LI penetration into the brain [4].
References:
[1] Grandjean EM, Aubry J-M. Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs. 2009;23(4):331–49.
[2] Vrijens B, Goetghebeur E. The impact of compliance in pharmacokinetic studies. Stat Methods Med Res. 1999 Sep;8(3):247–62.
[3] Kuhn E, Lavielle M. Maximum likelihood estimation in nonlinear mixed effects models. Comput Stat Data Anal. 2005 Jun 15;49(4):1020–38.
[4] Sproule B. Lithium in bipolar disorder: can drug concentrations predict therapeutic effect? Clin Pharmacokinet. 2002;41(9):639–60.
