Antimicrobial PK Simulator

A suite of tools for pharmacokinetic simulation and analysis, designed for preclinical-to-clinical dose translation of antimicrobial agents.

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Tools

Simulator (Setup / Plot / Table / Download)

What does the concentration-time profile look like for a given drug and dosing regimen?

Enter PK parameters and a dosing table to simulate concentration-time curves. Supports up to 4 drugs overlaid on the same plot (e.g., a BL + BLI combination). View PK/PD indices against MIC or CT thresholds. Download sampled data.

PK Fitting

Given observed concentration-time data, what are the best-fit PK parameters?

Paste or upload raw data. Fits 1- and 2-compartment models, performs NCA, compares models with AIC/BIC/F-test, and recommends the best fit. Transfer fitted parameters directly to other tools.

Allometric Scaling

What are the predicted human PK parameters from multi-species preclinical data?

HED (FDA Km): BSA-based Km conversion for inter-species dose scaling (safe starting dose for FIH).
PK Parameter Scaling: Power-law allometry (Y = a × BW ^b ) to predict human CL, Vc, Q, Vp from 2+ preclinical species. Import fitted parameters directly from PK Fitting. Transfer predictions to the Simulator or Dose Solver.

Dose Solver

What dose in a target species achieves the same PK exposure as a reference regimen?

Enter PK for both species. Solver matches by profile shape, fAUC₂₄, fCmax, or %fT>MIC. Useful for back-translating human regimens to animal models (or vice versa).

Dose Fractionation

How should a daily dose be split across dosing intervals to achieve a target %fT>CT?

Solves for dose at each candidate tau that maintains free drug above a threshold for a specified fraction of the interval. Useful for fractionation study design.

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General Workflow

1. Fit observed PK data per species → PK Fitting
2. Scale PK parameters to human → Allometric Scaling (PK Parameter Scaling)
3. Transfer predicted human params to the Simulator
4. Simulate and verify the profile → Plot / Table
5. Translate dose to another species → Dose Solver
6. Fractionate across intervals → Dose Fractionation

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Worked Example: BL + BLI Combination (e.g., Meropenem + MET-X)

This walkthrough illustrates an end-to-end PK-PD optimization workflow for a β-lactam / β-lactamase inhibitor combination, using AMRC-835 (a preclinical BLI candidate) as a concrete example. The same approach applies to any antimicrobial where preclinical PK data from multiple species is available.

Step 1: Fit Preclinical PK Data

Tab: PK Fitting

For each preclinical species (e.g., mouse, rat, dog), paste the observed concentration-time data and run the analysis.

• Set the correct dose amount and infusion duration (0 for IV bolus).
• The tool fits 1- and 2-compartment models and performs NCA. Use the recommended model's parameters (CL, Vc, and Q/Vp if 2-compartment).
• Example: Mouse IV bolus 15 mg/kg → fitted CL ≈ 20.5 mL/h, Vc ≈ 13.4 mL. Dog IV bolus 5 mg/kg → CL ≈ 1710 mL/h, Vc ≈ 3140 mL.

Step 2: Transfer Fitted Parameters to Allometric Scaling

Tab: Allometric Scaling → PK Parameter Scaling

After fitting each species, import the parameters into the allometric scaling table:

• On the PK Parameter Scaling sub-tab, use the "Import from PK Fitting as [Species]" button to pull fitted CL/Vc into the correct species row.
• Repeat for each species you have data for (minimum 2 species required).
• Body weights are pre-filled (Mouse: 0.02 kg, Rat: 0.15 kg, Dog: 10 kg). Adjust if your study used different weights.

Step 3: Predict Human PK Parameters

Tab: Allometric Scaling → PK Parameter Scaling

Click "Run Scaling" to fit the allometric power-law model (Y = a × BW ^b ) and predict human parameters at 70 kg.

• Check the exponents: CL ≈ 0.75, Vc ≈ 1.0 are typical. Exponents between 0.5 and 1.0 are generally acceptable.
• If you have ≥ 3 species, a 90% prediction interval is shown.
• Use the unit conversion dropdown if your preclinical data is in mL but the Simulator expects L (or vice versa).
• Example: From mouse + rat + dog CL (mL/h), predicted human CL ≈ 8359 mL/h (= 8.36 L/h after mL→L conversion).

Step 4: Simulate the Human PK Profile (BLI)

Tab: Setup → Plot

Click "Send to Simulator (Drug 1)" to transfer predicted human PK parameters.

• Set fu (fraction unbound) for your compound (e.g., 0.81 for MET-X, 0.98 for meropenem).
• Configure the dosing table: dose amount, infusion duration, interval (τ), and number of doses.
• Enter MIC or CT values as a comma-separated list (e.g., "0.5, 1, 4" for multiple thresholds).
• The Plot tab shows both total and free drug vs. time with MIC/CT reference lines.

Step 4b: Overlay the Partner β-Lactam (Drug 2)

Tab: Setup

For a BL + BLI combination, add the partner β-lactam as Drug 2:

• Increase the number of drugs to 2 on the Setup tab.
• Enter meropenem PK parameters for Drug 2 (from literature or your own fitting).
• Configure its dosing regimen (e.g., 1 g q8h, 90-min infusion).
• Both profiles are plotted together, showing whether both agents maintain adequate exposure simultaneously. For the combination to work, the BLI must stay above CT while the BL stays above MIC.

Step 5: Determine the Minimum Effective Dose

Tab: Dose Fractionation

Use Dose Fractionation to find the minimum dose that achieves a target %fT>CT at a given dosing interval:

• Transfer predicted human PK parameters to Dose Fractionation.
• Enter the target: e.g., %fT>CT = 50% at CT = 1 µg/mL for the BLI.
• The tool calculates the minimum dose for each candidate τ (e.g., q6h, q8h, q12h).
• Example: For AMRC-835 at CT = 4 µg/mL and 50% coverage, the predicted human dose was 342–443 mg q8h (3h infusion).

Step 6: Back-Translate to Animal Dosing

Tab: Dose Solver

To design an in vivo validation study (e.g., neutropenic thigh model), back-translate the human regimen to animal doses:

• Set the Reference (human) PK parameters and the desired regimen.
• Set the Target (mouse/rat) PK parameters from your preclinical fitting.
• Choose the matching mode (e.g., %fT>MIC or fAUC₂₄) to find the equivalent animal dose.
• The solver accounts for the faster clearance in smaller species, so doses and intervals will differ from the human regimen.

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Key PK-PD Targets for BL + BLI Combinations

Component	PK-PD Driver	Typical Target
β-Lactam (e.g., meropenem)	%fT>MIC	≥ 40–50% of dosing interval
BLI (e.g., avibactam, MET-X)	%fT>CT	≥ 20–50% of dosing interval

CT = critical threshold for BLI enzyme inhibition. When BLI drops below CT, enzymatic hydrolysis of the β-lactam resumes. Both targets must be met simultaneously for combination efficacy.