Metabolite models

Hi We are conducting a pragmatic pop-pk study following a single extravascular dose of an opioid in children. The parent molecule is rapidly hydrolysed to metabolite 1, which is subsequently hydrolysed to metabolite 2. Metabolite 2 is metabolised to metabolite 3 and 4, but also partially renally excreted. The plasma is being bioanalysed for metabolite 1 to 4, but not the parent (latter has a half-life of 2-3 mins, and is not known to contribute significantly to PD). Typically, we are managing to get between 3- 4 samples per subject and hope to recruit approx. 75 children. We are part way through the study and have done an interim bioanalysis. I have two model development questions as I plan my analysis:- 1. Since parent is not being measured, how would you parameterise the formation of metabolite 1? i.e. since the appearance of metabolite 1 is a 'two-step' process, absorption of drug and subsequent hydrolysis, would you consider using previous literature reported estimates of absorption rate to estimate formation clearance of metabolite 1, or is it more sensible to estimate the composite parameter (absorption + formation clearance)? 2. It is clear from the interim bioanalysis, that we are not sampling our far enough to observe the elimination phase of metabolite 3 and 4 i.e. I'm only seeing accumulation. This is a pragmatic hospital study so it is unlikely that I can persuade the clinicians / nurses / patients to generate later samples. With that in mind is there any mileage in including metabolite 3 and 4 in the model? Regards Hussain Hussain Mulla Senior Research Pharmacist Department of Pharmacy University Hospitals of Leicester NHS Trust Glenfield Hospital Groby Road Leicester LE3 9QP Tel: 0116 2502708 This e-mail, including any attached files, may contain confidential and / or privileged information and is intended for the exclusive use of the addressee(s) printed above. If you are not the addressee(s), any unauthorised review, disclosure, reproduction, other dissemination or use of this e-mail, or taking of any action in reliance upon the information contained herein, is strictly prohibited. If this e-mail has been sent to you in error, please return to the sender. No guarantee can be given that the contents of this email are virus free - The University Hospitals of Leicester NHS Trust cannot be held responsible for any failure by the recipient(s) to test for viruses before opening any attachments. The information contained in this e-mail may be the subject of public disclosure under the Freedom of Information Act 2000 - unless legally exempt from disclosure, the confidentiality of this e-mail and your reply cannot be guaranteed. Copyright in this email and any attachments created by us remains vested in the University Hospitals of Leicester NHS Trust.