PKIS v2.0 A clinical tool for identifying important pharmacokinetic drug-drug interactions

Overview

P
harmacoKinetic Interaction Screening (PKIS) can be used to simplify the identification of potential pharmacokinetic drug-drug interactions (PK-DDIs) in clinical practice. PK-DDIs occur when a "perpetrator" drug modifies the pharmacokinetics of an "object" drug leading to changes in its blood concentration. This may lead to toxicity resulting in patient harm or sub-therapeutic concentrations resulting in loss of efficacy. This version of PKIS considers PK-DDIs mediated by cytochrome P450 metabolism.

Premises

  1. Any DDIs between existing drugs in a given patient have already occurred (thus relevant to differential diagnoses rather than prescribing).
  2. Recognition of potential pharmacodynamic DDIs is based on knowledge of both the pharmacological effects of the drugs and the physiology of the patient at the time of prescribing.
  3. A small number of drugs are important ‘perpetrators’ of PK-DDIs.
  4. Starting or stopping a drug is a prescribing decision that may cause a DDI.

Aim

To provide an up-to-date clinically relevant resource that supports clinical decisions on PK-DDIs. PKIS (V2.0) can be used to:
  1. Quickly identify the major perpetrators of CYP-mediated PK-DDIs that are capable of causing 2-fold changes in the concentrations of other drugs.
  2. Assess the potential of any drug to act as a perpetrator of CYP-mediated PK-DDIs.
  3. Review the clinical PK interaction literature on CYP inhibitors and inducers.

Inclusion criteria

Candidate drugs are assessed as potential perpetrators of PK-DDIs using the following inclusion criteria:
  1. Clinical pharmacokinetic (PK) interaction studies in humans (n≥6)
  2. use of an appropriate in vivo CYP probe (fraction of the probe metabolised by the CYP > 0.8);
    • CYP1A2: caffeine, theophylline, or tizanidine
    • CYP2C9: phenytoin, S-warfarin, or tolbutamide
    • CYP2C19: mephenytoin, or omeprazole
    • CYP2D6: debrisoquine, desipramine, dextramethorphan, metoprolol, or sparteine
    • CYP3A: buspirone, maraviroc, midazolam, triazolam, or simvastatin
  3. clinically relevant dosing of perpetrator (until steady-state for drugs taken chronically or the typical clinical regimen).
Drugs with studies that meet these criteria are considered to have Level A Evidence.

Classification criteria

In order of preference, drugs are classified based on changes in:
  1. the area under the plasma concentration-time curve (AUC) of selective CYP probes
  2. total systemic clearance of selective CYP probes
  3. plasma or urinary metabolite ratios of selective CYP probes
In accordance to FDA classifications:
  • Inhibitors: Strong, moderate, and weak
  • Inducers: Strong (≥ 2-fold decrease in AUC), Weak ( <2-fold decrease in AUC)
A. Accepted major perpetrators (with Level A Evidence):
  • strong inhibitors
  • moderate inhibitors
  • strong inducers
  • B. Rejected major perpetrators (with Level A Evidence):
  • weak inhibitors
  • weak inducers
  • drugs that do not alter the clearance of probes
  • drugs not available in Australia or New Zealand
  • C. Unclassifiable perpetrators (without Level A evidence) comprised drugs with:
  • studies that did not meet the criteria
  • studies that could not be formally assessed
  • no clinical PK interaction data.
  • Disclaimer
    WARNING: While all efforts were put in to maintain the accuracy and currency of the information, it is possible that the knowledge and electronic tools may contain errors and inadequacy. Both Flinder's University and University of New South Wales are not liable to any damages or losses resulted from such circumstances. Clinical discretions are strongly advised at all times.