Drug Dosing Parameters
The four parameters associated with dosing are:
- Dose, \(D\), the amount of drug
- Interval, \(\tau\), the frequency of administration
- Number of doses, \(N_{doses}\)
- Route, the route of administration, such as IV or SC.
Dose, interval, and route for existing drugs can generally be found in prescribing information. It could also be set to a maximum feasible dose based on a therapeutic concept.
Dose Amount in Assess
Dose refers to the dose amount to be administered. For most models, it can be entered in units of mg or mg/kg. In models of in vitro experiments, the dose can also be set in terms of nanomoles. If entered in units of mg/kg, a total dose (mg) will be calculated from the entered body weight parameter (BW, kg).
In Assess, an analysis is frequently framed as "for a given set of parameters, does the model predict an acceptable dose?" In this case, dose is a scanned parameter, which can be set in the Feasibility Settings tab. For example, to set up a simulation to answer the question: What is the minimum dose necessary to reach a particular Target Engagement threshold?, one would set up a scan of the Dose parameter, enter a range, and run the scenario to determine the answer. If a reasonable dose range has not been defined a priori, a wide range (from < 1 mg or < 0.01 mg/kg to > 7000 mg or > 100 mg/kg) can be scanned.
Interval in Assess
Interval defines the interval of time between simulated doses. For drugs dosed multiple times, options for interval include
- QD: dosing every 24 hours
- TIW: every other day
- BIW: every 3.5 days
- Q1W: once per week
- Q2W: once every two weeks
- Q3W: once every three weeks
- Q1M: once every four weeks
- Q2M: once every eight weeks
- Q3M: once every 12 weeks
The length of the simulation is determined by the dosing interval and number of doses. The route of administration and desired dosing frequency is often a component of the target product profile (TPP). Examples of dosing frequency of clinically approved drugs:
| Drug | Indication | Dosing frequency / route of administration |
|---|---|---|
| Remicase (infliximab) | RA | 8 weeks IV |
| Humira (adalimumab) | RA | 2 weeks SC |
| Stelara (ustekinumab) | Plaque psoriasis | 12 weeks SC |
| Skyrizi (risankizumab) | Plaque psoriasis | 12 weeks SC / 4 weeks SC |
| Benlysta (belimumab) | SLE | 1 week SC / 4 weeks IV |
| Xolair (omalizumab) | Asthma | 2 weeks SC |
| Herceptin (trastuzumab) | Breast cancer | 1 week IV |
| Vectibix (panitumumab) | Colon cancer | 2 weeks IV |
| Rybrevant (amivantamab) | NSCLC (EGFR exon 2) | 2 weeks IV |
Table adapted from Marcantonio et. al. 2022.
Number of Doses
Most commonly, Assess is used to understand steady-state pharmacodynamics. The number of doses can impact the results of an analysis in Assess through accumulation effects. Seven repeated doses is generally sufficient to reach a steady-state pharmacokinetic profile in the absence of significant target mediated clearance or strong accumulation effects. If the PK or PD profiles indicate that accumulation is still happening at the end of a time course, \(N_{doses}\) may need to be increased to support a steady-state analysis.
References
- Marcantonio, Diana H., Andrew Matteson, Marc Presler, John M. Burke, David R. Hagen, Fei Hua, and Joshua F. Apgar. 2022. "Early Feasibility Assessment: A Method for Accurately Predicting Biotherapeutic Dosing to Inform Early Drug Discovery Decisions." Frontiers in Pharmacology 13. https://doi.org/10.3389/fphar.2022.864768.