Compare Protocols

Semaglutide: drug concentration in plasma (nmol/L).

Fixed reference profile: Published reference: 85 kg white, non-Hispanic female under 65 with type 2 diabetes and normal renal function. Subcutaneous semaglutide solution in the SUSTAIN phase III program; Subcutaneous. Fixed reference weight: 85 kg.

Changing dose or schedule explores a scenario; it does not personalize the reference profile or establish a studied regimen.

Input dose basis: Milligrams of semaglutide, not solution volume, syringe units or a salt/product conversion.

Source exposure scope: Published phase III maintenance groups were 0.5 and 1 mg weekly. Other amounts or timings are mathematical extrapolations of this fixed reference.

Published one-compartment reference: 85 kg adult with type 2 diabetes

semaglutide-petri-2018-fixed-reference · version 1

• Abdominal administration; all reference covariate factors and individual random effects fixed at their reference values.
• The source 1 mg maintenance-group clearance is held fixed when the entered amount changes; dose-group and other covariate effects are not implemented.
• Apparent clearance and volume already incorporate bioavailability; no additional availability factor is applied.
• Zero pre-existing semaglutide before the entered dose history; first-order absorption and linear elimination.

Model structure

One compartment with absorption

Apparent clearance (CL/F)

0.0478 L/hour

Apparent central volume (Vc/F)

12.2 L

Absorption rate (ka)

0.0286 /hour

Input mass conversion

1 mg modelled mass per mg entered

• This is a fixed reference calculation, not an individual blood-level prediction or the full published covariate model.
• The source used sparse steady-state samples and fixed absorption. Initial-dose peak timing is a model extrapolation, not a verified patient-specific endpoint.
• Oral semaglutide, compounded preparations and formulation changes are outside this model; approval of a product does not validate a different formulation.
• Concentration does not predict weight loss, glucose response, tolerability or a safe dose. A clearance threshold is not a safety or testing guarantee.

• Petri et al. 2018 — semaglutide population pharmacokinetics

  Methods: fixed ka 0.0286/h and reference covariates. Results / Table S3: reference CL/F 0.0478 L/h and V/F 12.2 L. Apparent parameters are used directly.

• Overgaard et al. 2019 — clinical pharmacokinetics of semaglutide

  Table 5 independently lists the previous phase III one-compartment parameters. The separate two-compartment parameters are not mixed into this reference.

• Novo Nordisk Ozempic prescribing information

  Section 11 supplies molecular weight for mass-to-molar conversion. Label population exposure is a secondary comparison, not a fitted single-dose peak.

Tirzepatide: drug concentration in plasma (nmol/L).

Fixed reference profile: Constructed adult female reference with type 2 diabetes: 90 kg and BMI 32.5 kg/m²; not a published average participant. Subcutaneous tirzepatide in the published pooled-study model, using its estimated relative-bioavailability scenario; Subcutaneous. Fixed reference weight: 90 kg.

Changing dose or schedule explores a scenario; it does not personalize the reference profile or establish a studied regimen.

Input dose basis: Milligrams of tirzepatide, not solution volume, syringe units or a product conversion.

Source exposure scope: The source pooled single and repeated subcutaneous dosing across phase I–III studies. Entered schedules are simulations, not treatment instructions.

Published two-compartment model: constructed 90 kg female reference

tirzepatide-schneck-2024-fixed-reference · version 1

• Body weight, sex and BMI stay fixed. Fat-free mass 49.9282 kg and fat mass 40.0718 kg are calculated from the published female equation.
• Clearance and intercompartmental clearance scale with (90/70)^0.8; both volumes scale with (fat-free mass + 0.482 × fat mass)/70.
• Effective availability is 0.8 × (1 − 0.181) = 0.6552, the supplementary model setting for pooled studies other than the phase-I absolute-bioavailability reference study (STUDYN=4). It is applied once.
• Individual random effects are zero. No weight-loss trajectory or pre-existing tirzepatide is assumed before the entered dose history.

Model structure

Two compartments with absorption

Clearance (CL)

0.04022643 L/hour

Central volume (Vc)

2.443282 L

Absorption rate (ka)

0.0373 /hour

Intercompartmental clearance (Q)

0.1540587 L/hour

Peripheral volume (Vp)

3.936948 L

Bioavailability (F)

65.52%

Input mass conversion

1 mg modelled mass per mg entered

• This is a fixed scenario from the published population model, not an individual prediction or a published mean concentration profile.
• The source allowed body weight to change over time; this implementation freezes body size and does not simulate parameter variability or uncertainty bands.
• The between-study availability term is model context, not evidence that every marketed, compounded or investigational formulation shares this availability.
• Concentration does not predict treatment response, tolerability or a safe dose. A clearance threshold is not a safety or testing guarantee.

• Schneck and Urva 2024 — population pharmacokinetics of tirzepatide

  Table 3 and equations 5–8: two-compartment coefficients, female fat-free mass, total-weight clearance scaling, adjusted-fat-mass volume scaling and F = 0.8 × (1 − 0.181). Parameters here are derived for the explicitly constructed reference.

• Lilly Mounjaro prescribing information

  Section 11 supplies molecular weight for mass-to-molar conversion. Label mean apparent clearance and volume are population summaries, not interchangeable structural coefficients.

• Schneck and Urva — supplementary executable model

  Supplementary Attachment 2 NONMEM: BIOPHS=1+THETA(10), except STUDYN=4. Table 3 Vp=3.98 L/70 kg is used here, versus 3.97 in the supplementary code; this source-version discrepancy is retained explicitly.