Separation of the PK parameters for mixed endogenous and exogenous substances.

On 05-10-2024 09:02, karam alali wrote: > Dear NONMEM users, > > I encountered a case when an endogenous substance and an exogenous substance were not separated by any analytical method or using isotopes, which means we have a mix of both substances in the central compartment. > > 1. What are the possible methods to predict their pharmacokinetics? > > 2. Is it valid to use the clearance and volume of distribution of the total substance? 3. if I use the central compartment for the endogenous substance DADTendo (which contains the total) and create a dummy compartment for the exogenous substance DADTexo, would then be possible to account separately for each of their pharmacokinetics (CL, V) when we set the IPRED = A(endo) + A(exo)? > > Note: the endogenous substances are not in a steady state > > Regard > > Karam Alali > PhD Candidate > Clinical Pharmacy Discipline > Universiti Sains Malaysia

On Sun, Oct 6, 2024 at 4:18 PM karam alali <[email protected]> wrote: > Thanks for your reply Jeroen, > > This is an interesting approach to use the circadian rhythm of cortisol > and then the inhibition function of exogenous hydrocortisone to link the > two substances. However, if I do not have enough data (one point at time > zero, then a few points after the dose, not a 24h data), do you think I can > apply the same coding for the circadian rhythm (they used 4 harmonics)? If > you have a reference for coding the circadian rhythm, that would be useful. > > Best Regards > > Karam Alali > PhD Candidate > Clinical Pharmacy Discipline > Universiti Sains Malaysia > > On Sat, Oct 5, 2024 at 3:41 PM Jeroen Elassaiss-Schaap (PD-value B.V.) < > [email protected]> wrote: > >> Dear Karem, >> >> The short answer is that it is possible to set up an useful PK model in >> this circumstance. The focus however will be to describe the endogenous >> substance with sufficient detail and quality. Only once you have done >> that properly you can derive a meaningful PK model for the exogenous >> substance. >> >> An example can be found in the work of the Jusko group on cortisol, >> which is both a non-steady state biomarker and a drug (but more >> complicated because of feedback). See eg the Mager2013 paper: >> https://doi.org/10.1177/0091270003258651 >> >> Hope this helps, >> >> Jeroen >> >> >> http://pd-value.com >> [email protected] >> @PD_value >> +31 6 23118438 >> -- More value out of your data! >> >> On 05-10-2024 09:02, karam alali wrote: >> > Dear NONMEM users, >> > >> > I encountered a case when an endogenous substance and an exogenous >> > substance were not separated by any analytical method or using >> > isotopes, which means we have a mix of both substances in the central >> > compartment. >> > >> > 1. What are the possible methods to predict their pharmacokinetics? >> > 2. Is it valid to use the clearance and volume of distribution of the >> > total substance? >> > 3. if I use the central compartment for the endogenous substance >> > DADTendo (which contains the total) and create a dummy compartment for >> > the exogenous substance DADTexo, would then be possible to account >> > separately for each of their pharmacokinetics (CL, V) when we set the >> > IPRED = A(endo) + A(exo)? >> > >> > Note: the endogenous substances are not in a steady state >> > >> > Regard >> > >> > Karam Alali >> > PhD Candidate >> > Clinical Pharmacy Discipline >> > Universiti Sains Malaysia >> >

________________________________ From: karam alali <[email protected]> Sent: Sunday, October 6, 2024 10:31 To: [email protected] Subject: Re: [NMusers] Separation of the PK parameters for mixed endogenous and exogenous substances. Thanks for your reply Jeroen, This is an interesting approach to use the circadian rhythm of cortisol and then the inhibition function of exogenous hydrocortisone to link the two substances. However, if I do not have enough data (one point at time zero, then a few points after the dose, not a 24h data), do you think I can apply the same coding for the circadian rhythm (they used 4 harmonics)? If you have a reference for coding the circadian rhythm, that would be useful. Best Regards Karam Alali PhD Candidate Clinical Pharmacy Discipline Universiti Sains Malaysia On Sun, Oct 6, 2024 at 4:18 PM karam alali <[email protected]<mailto:[email protected]>> wrote: Thanks for your reply Jeroen, This is an interesting approach to use the circadian rhythm of cortisol and then the inhibition function of exogenous hydrocortisone to link the two substances. However, if I do not have enough data (one point at time zero, then a few points after the dose, not a 24h data), do you think I can apply the same coding for the circadian rhythm (they used 4 harmonics)? If you have a reference for coding the circadian rhythm, that would be useful. Best Regards Karam Alali PhD Candidate Clinical Pharmacy Discipline Universiti Sains Malaysia On Sat, Oct 5, 2024 at 3:41 PM Jeroen Elassaiss-Schaap (PD-value B.V.) <[email protected]<mailto:[email protected]>> wrote: Dear Karem, The short answer is that it is possible to set up an useful PK model in this circumstance. The focus however will be to describe the endogenous substance with sufficient detail and quality. Only once you have done that properly you can derive a meaningful PK model for the exogenous substance. An example can be found in the work of the Jusko group on cortisol, which is both a non-steady state biomarker and a drug (but more complicated because of feedback). See eg the Mager2013 paper: https://doi.org/10.1177/0091270003258651 Hope this helps, Jeroen http://pd-value.com [email protected]<mailto:[email protected]> @PD_value +31 6 23118438 -- More value out of your data! On 05-10-2024 09:02, karam alali wrote: > Dear NONMEM users, > > I encountered a case when an endogenous substance and an exogenous > substance were not separated by any analytical method or using > isotopes, which means we have a mix of both substances in the central > compartment. > > 1. What are the possible methods to predict their pharmacokinetics? > 2. Is it valid to use the clearance and volume of distribution of the > total substance? > 3. if I use the central compartment for the endogenous substance > DADTendo (which contains the total) and create a dummy compartment for > the exogenous substance DADTexo, would then be possible to account > separately for each of their pharmacokinetics (CL, V) when we set the > IPRED = A(endo) + A(exo)? > > Note: the endogenous substances are not in a steady state > > Regard > > Karam Alali > PhD Candidate > Clinical Pharmacy Discipline > Universiti Sains Malaysia

On 6 Oct 2024, at 09:34, karam alali <[email protected]> wrote:  You don't often get email from [email protected]. Learn why this is https://aka.ms/LearnAboutSenderIdentification This message originated from outside of NHSmail. Please do not click links or open attachments unless you recognise the sender and know the content is safe. Thanks for your reply Jeroen, This is an interesting approach to use the circadian rhythm of cortisol and then the inhibition function of exogenous hydrocortisone to link the two substances. However, if I do not have enough data (one point at time zero, then a few points after the dose, not a 24h data), do you think I can apply the same coding for the circadian rhythm (they used 4 harmonics)? If you have a reference for coding the circadian rhythm, that would be useful. Best Regards Karam Alali PhD Candidate Clinical Pharmacy Discipline Universiti Sains Malaysia On Sun, Oct 6, 2024 at 4:18 PM karam alali <[email protected]<mailto:[email protected]>> wrote: Thanks for your reply Jeroen, This is an interesting approach to use the circadian rhythm of cortisol and then the inhibition function of exogenous hydrocortisone to link the two substances. However, if I do not have enough data (one point at time zero, then a few points after the dose, not a 24h data), do you think I can apply the same coding for the circadian rhythm (they used 4 harmonics)? If you have a reference for coding the circadian rhythm, that would be useful. Best Regards Karam Alali PhD Candidate Clinical Pharmacy Discipline Universiti Sains Malaysia On Sat, Oct 5, 2024 at 3:41 PM Jeroen Elassaiss-Schaap (PD-value B.V.) <[email protected]<mailto:[email protected]>> wrote: Dear Karem, The short answer is that it is possible to set up an useful PK model in this circumstance. The focus however will be to describe the endogenous substance with sufficient detail and quality. Only once you have done that properly you can derive a meaningful PK model for the exogenous substance. An example can be found in the work of the Jusko group on cortisol, which is both a non-steady state biomarker and a drug (but more complicated because of feedback). See eg the Mager2013 paper: https://doi.org/10.1177/0091270003258651 Hope this helps, Jeroen http://pd-value.com/ [email protected]<mailto:[email protected]> @PD_value +31 6 23118438 -- More value out of your data! On 05-10-2024 09:02, karam alali wrote: > Dear NONMEM users, > > I encountered a case when an endogenous substance and an exogenous > substance were not separated by any analytical method or using > isotopes, which means we have a mix of both substances in the central > compartment. > > 1. What are the possible methods to predict their pharmacokinetics? > 2. Is it valid to use the clearance and volume of distribution of the > total substance? > 3. if I use the central compartment for the endogenous substance > DADTendo (which contains the total) and create a dummy compartment for > the exogenous substance DADTexo, would then be possible to account > separately for each of their pharmacokinetics (CL, V) when we set the > IPRED = A(endo) + A(exo)? > > Note: the endogenous substances are not in a steady state > > Regard > > Karam Alali > PhD Candidate > Clinical Pharmacy Discipline > Universiti Sains Malaysia ************************************************************************************** ****************************** This message may contain confidential information. If you are not the intended recipient please: i) inform the sender that you have received the message in error before deleting it; and ii) do not disclose, copy or distribute information in this e-mail or take any action in relation to its content (to do so is strictly prohibited and may be unlawful). Thank you for your co-operation. NHSmail is the secure email, collaboration and directory service available for all NHS staff in England. NHSmail is approved for exchanging patient data and other sensitive information with NHSmail and other accredited email services. For more information and to find out how you can switch visit Joining NHSmail – NHSmail https://support.nhs.net/article-categories/joining-nhsmail/