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Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate

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Abstract

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.

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Abbreviations

6-MP:

6-Mercaptopurine

MTX:

Methotrexate

ALL:

Acute lymphoblastic leukaemia

PK:

Pharmacokinetics

PBPK:

Physiologically based pharmacokinetic

RBC:

Red blood cell

XO:

Xanthine oxidase

HPRT:

Hypoxanthine phosphoribosyltransferase

TPMT:

Thiopurine methyltransferase

6-TGN:

6-Thioguanine nucleotides

6-mMPN:

6-Methylmercaptopurine nucleotide

BSA:

Body surface area

BW:

Body weight

HT:

Height

AUC:

Area under the concentration

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Acknowledgments

This work performed as part of Child-Rare-Euro-Simulation project. CRESim was funded by the ERA-NET PRIOMEDCHILD Joint Call in 2010. The authors also acknowledge helpful discussions with Dr. Aleksandra Galetin, Dr. Michael Gertz, Dr. Eleanor Howgate, Dr. Henry Pertinez, Mr. Nikolaos Tsamandouras, Mr. Adam Darwich and member of Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School. Members of the CRESim Project Group: Leon Aarons; Agathe Bajard; Clément Ballot; Yves Bertrand; Frank Bretz; Daan Caudri; Charlotte Castellan; Sylvie Chabaud; Catherine Cornu; Frank Dufour; Nathalie Eymard; Roland Fisch; Renzo Guerrini; Vincent Jullien; Behrouz Kassaï; Patrice Nony; Kayode Ogungbenro; David Pérol; Gérard Pons; Harm Tiddens; Anna Rosati. Members of the Epi-CRESim Project Group: Corinne Alberti; Catherine Chiron; Catherine Cornu, Polina Kurbatova; Rima Nabbout.

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Correspondence to Kayode Ogungbenro.

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The members of The CRESim & Epi-CRESim Project Groups is listed in Acknowledgment

Appendix 1

Appendix 1

Equations that describe the concentration in each tissue/organ of the PBPK model for 6-mercaptopurine

(1) Systemic plasma

$$\begin{gathered} V_{P} \frac{{dC_{P} }}{dt} = \left( {Q_{HE} + Q_{GUT} + Q_{ENT} + Q_{SP} } \right)C_{LIV,V} + Q_{KID} C_{KID,V} + \frac{{Q_{MU} C_{MU} }}{{K_{p,MU} }} + \frac{{Q_{SK} C_{SK} }}{{K_{p,SK} }} + \frac{{Q_{BM} C_{BM} }}{{K_{p,BM} }} + \frac{{Q_{TH} C_{TH} }}{{K_{p,TH} }} + \frac{{Q_{RE} C_{RE} }}{{K_{p,RE} }} \hfill \\ + Q_{HE} + Q_{GUT} + Q_{ENT} + Q_{KID} + Q_{MU} + Q_{SK} + Q_{SP} + Q_{BM} + Q_{TH} + Q_{RE} )C_{P} - CLPLASC_{P} - PSBCfuC_{P} + PSBCC_{RBC,U} \hfill \\ \end{gathered}$$

(2) Muscle

$$V_{MU} \frac{{dC_{MU} }}{dt} = Q_{MU} \left( {C_{P} - \frac{{C_{MU} }}{{K_{p,MU} }}} \right)$$

(3) Kidney

Vascular

$$V_{KID,V} \frac{{dC_{KID,V} }}{dt} = Q_{KID} \left( {C_{P} - C_{KID,V} } \right) - CLPASS_{KID} fuC_{KID,V} + \frac{{CLPASS_{KID} fuC_{KID,T} }}{{K_{p,KID} }}$$

Tissue

$$V_{KID,T} \frac{{dC_{KID,T} }}{dt} = CLPASS_{KID} fuC_{KID,V} - \frac{{CLPASS_{KID} fuC_{KID,T} }}{{K_{p,KID} }}$$

(4) Liver

Vascular

$$\begin{gathered} V_{LIV,V} \frac{{dC_{LIV,V} }}{dt} = Q_{HE} \left( {C_{P} - C_{LIV,V} } \right) - CLPASS_{LIV} fuC_{LIV,V} + \frac{{CLPASS_{LIV} fuC_{LIV,T} }}{{K_{p,LIV} }} + \frac{{\left( {Q_{GUT} + Q_{ENT} } \right)C_{GUT} }}{{K_{p,GUT} }} \hfill \\ - \left( {Q_{GUT} + Q_{ENT} } \right)C_{LIV,V} + \frac{{Q_{SP} C_{SP} }}{{K_{p,SP} }} - Q_{SP} C_{LIV,V} + Q_{ENT} C_{ENT} \hfill \\ \end{gathered}$$

Tissue

$$V_{LIV,T} \frac{{dC_{LIV,T} }}{dt} = CLPASS_{LIV} fuC_{LIV,V} - \frac{{CLPASS_{LIV} fuC_{LIV,T} }}{{K_{p,LIV} }} - \frac{{CLL_{XO} fuC_{LIV,T} }}{{K_{p,LIV} }}$$

(5) Gut

Tissue

$$V_{GUT} \frac{{dC_{GUT} }}{dt} = \left( {Q_{GUT} + Q_{ENT} } \right)\left( {C_{P} - \frac{{C_{GUT} }}{{K_{p,GUT} }}} \right)$$

Lumen

$$\frac{{dA_{LUM} }}{dt} = kgA_{ST} - kaA_{LUM} - ktA_{LUM}$$

Enterocyte

$$V_{ENT} \frac{{dC_{ENT} }}{dt} = kaA_{LUM} - Q_{ENT} C_{ENT} - CLG_{XO} C_{ENT}$$

(6) Stomach

$$\frac{{dA_{ST} }}{dt} = - kgA_{ST}$$

(7) Skin

$$V_{SK} \frac{{dC_{SK} }}{dt} = Q_{SK} \left( {C_{P} - \frac{{C_{SK} }}{{K_{p,SK} }}} \right)$$

(8) Bone Marrow

$$V_{BM} \frac{{dC_{BM} }}{dt} = Q_{BM} \left( {C_{P} - \frac{{C_{BM} }}{{K_{p,BM} }}} \right)$$

(9) Spleen

$$V_{SP} \frac{{dC_{SP} }}{dt} = Q_{SP} \left( {C_{P} - \frac{{C_{SP} }}{{K_{p,SP} }}} \right)$$

(10) Thymus

$$V_{TH} \frac{{dC_{TH} }}{dt} = Q_{TH} \left( {C_{P} - \frac{{C_{TH} }}{{K_{p,TH} }}} \right)$$

(11) Rest of the body

$$V_{RE} \frac{{dC_{RE} }}{dt} = Q_{RE} \left( {C_{P} - \frac{{C_{RE} }}{{K_{p,RE} }}} \right)$$

(12) Red blood cell

$$\begin{gathered} V_{RBC} \frac{{dC_{RBC} }}{dt} = PSBCfuC_{P} - PSBCC_{RBC,U} \hfill \\ C_{RBC,U} = \left( {\sqrt {\left( {\left( {nP + K_{D} - C_{RBC} } \right)^{2} + \left( {4K_{D} C_{RBC} } \right)} \right)} - \left( {K_{D} + nP - C_{RBC} } \right)} \right)/2 \hfill \\ \end{gathered}$$

6-MP and MTX interaction

Enterocyte

$$V_{ENT} \frac{{dC_{ENT,6MP} }}{dt} = ka_{6MP} A_{LUM,6MP} - Q_{ENT} C_{ENT,6MP} - \left( {\frac{{C_{ENT,6MP} CLG_{XO} }}{{1 + C_{ENT,MTX} /Ki}}} \right)$$

Liver tissue

$$V_{LIV,T} \frac{{dC_{LIV,T(6MP)} }}{dt} = CLPASS_{LIV} fu_{6MP} C_{LIV,V(6MP)} - \frac{{CLPASS_{LIV} fu_{6MP} C_{LIV,T(6MP)} }}{{K_{p,LIV(6MP)} }} - \frac{{CLL_{XO} fu_{6MP} C_{LIV,T(6MP)} /K_{p,LIV(6MP)} }}{{1 + C_{LIV,T(MTX)} fu_{MTX} /Ki}}$$

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Ogungbenro, K., Aarons, L. & The CRESim & Epi-CRESim Project Groups. Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate. J Pharmacokinet Pharmacodyn 41, 173–185 (2014). https://doi.org/10.1007/s10928-014-9355-3

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