NONMEM and Bioavailability fraction

Dear NM users I am running an extravascular pop PK model with dual absorption and got the following message from NM: [cid:[email protected]] Has anyone experienced the same issue and how to fix it? Thank you in advance for your help Marie

Hi Marie, The message "PK PARAMETER FOR BIOAVAILABILITY FRACTION IS NEGATIVE" indicates the source of your issue, but it can be misleading as NONMEM can also report this error message if the bioavailability parameter is 0. I would suggest that you look at the parameterization of your bioavailability parameter (F1, F2, etc...) and check if the value can be set to 0 or negative values (particularly if you have an IIV term on it)... Maybe share your full model code if you are not sure how to fix the issue. Sebastien Regeneron - Internal Regeneron - Internal

Dear Marie, You might want to share a snippet of your control stream for further help. You may want to set a lower boundary of 0 for your estimate of F in the $THETA block and if you allow inter-individual variability, you may want to do a logit transformation of your bioavailability parameter and its variability, to constrain the value between 0-1. Sincerely, Rob Van: [email protected] <[email protected]> namens Marie Rajerison <[email protected]> Datum: dinsdag, 11 maart 2025 om 15:01 Aan: [email protected] <[email protected]>, [email protected] <[email protected]> Onderwerp: [NMusers] RE: NONMEM and Bioavailability fraction Dear NM users I am running an extravascular pop PK model with dual absorption and got the following message from NM: [cid:[email protected]] Has anyone experienced the same issue and how to fix it? Thank you in advance for your help Marie De informatie in dit bericht is uitsluitend bestemd voor de geadresseerde. Aan dit bericht en de bijlagen kunnen geen rechten worden ontleend. Heeft u deze e-mail onbedoeld ontvangen? Dan verzoeken wij u het te vernietigen en de afzender te informeren. Openbaar maken, kopi?ren en verspreiden van deze e-mail of informatie uit deze e-mail is alleen toegestaan met voorafgaande schriftelijke toestemming van de afzender. Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het handelsregister onder nummer 80262783. The content of this message is intended solely for the addressee. No rights can be derived from this message or its attachments. If you are not the intended recipient, we kindly request you to delete the message and inform the sender. It is strictly prohibited to disclose, copy or distribute this email or the information inside it, without a written consent from the sender. Radboud university medical center is registered with the Dutch Chamber of Commerce trade register with number 80262783.

To avoid negative F, you can use logit transformation to define F. may need to show your nm code to understand the problem. Sam

Not the same issue, but issues of a similar nature. Most of the time, it is due to a discrepancy between the model structure and the dataset. Among ChatGPT's suggestions below, and I would bet on #1 (relative F between the two formulations not defined correctly): 1. Bioavailability Fraction Parameter: Ensure that the bioavailability fraction (F) parameter is correctly defined in the $PK record. A negative value might indicate an issue with how the parameter is calculated or defined in the model. 2. Dataset Errors: Verify that your dataset is correctly formatted. Non-numeric cells, NA values, and unsorted time columns can cause errors in NONMEM. Ensure that all cells in the dataset are numeric and properly formatted. 3. Additional Parameters: Check the additional parameters in your model, such as absorption lag time, relative bioavailability fraction, rate parameter for zero-order input, duration parameter of that input, and scaling parameter. Incorrect specification or estimation of these parameters can lead to errors. Cheng