Tirzepatide Titration (24 weeks)

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.