Is HPAPI also a Low PDE?

Ester Lovsin Barle*
Department of Novartis Pharma AG, Postfach, Switzerland

*Corresponding author: Ester Lovsin Barle, Department of Novartis Pharma AG, Postfach, Switzerland

Published: 06 Jan, 2017
Cite this article as: Barle EL. Is HPAPI also a Low PDE?. Ann Pharmacol Pharm. 2017; 2(1): 1009.


Potency is determined by the dose of the drug required to produce an effect. A highly potent drug (e.g., fentanyl, estrogen, calcitriol) evokes a desires pharmacological response in target population of patients at low concentrations. On the other hand, these drugs may also evoke unintended, adverse effects at doses lower than the intended effects. These effects may be acceptable in the patient population; however they are not acceptable in other populations, such as workers, or patients who would receive such a drug as a contaminant. Due to these differences, defining an HPAPI is not uniform.
The definition of an HPAPI varies significantly in the literature. The following definitions may be found:
1. DS or IM with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg).
2. DS or IM with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average.
3. DS or IM with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, target organ effects or reproductive toxicity at low doses.
4. Or, by default, a novel compound of unknown potency and toxicity [1].
In their GMP guidelines, regulatory agencies sometimes include the following sentence: “The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities.” However they leave the assessment of the definitions for these terms to the individuals.
Permitted Daily Exposure (PDE) is presently not included in the definitions of highly potent or highly active. To understand if a PDE value can be an indicator of a HPAPI, we must understand how the PDEs are derived.
For the purposes of PDE calculation based on toxicological criteria, a critical effect needs to be identified; in this context any effect is an adverse effect, on target or off target. Identification of the critical effect requires comprehensive evaluation of all relevant data and identifies the no-observed-adverse-effect level (NOAEL) for the critical effect, also termed as point of departure (POD) for the PDE calculation (Figure 1) [2].
PDE [μg/day] = POD [mg/kg/day] × BW [kg] ÷ Composite Adjustment Factor (CAF) × 1000
OELs are calculated in a very similar way; the critical difference is in the determination of the critical effect for the target population of healthy workers vs. [3,4] patients, followed by modification of AFs to adjust for this criterion. Also the OEL is expressed in ug/m3 to extrapolate to the volume of air inhaled in 8h working time (10 m3). Therefore OEL (in ug/m3) is typically 10x lower than a PDE (in ug/ day).
Similarly to the OEL PDE values fall into a range that spans over several orders of magnitude. In a study done with over 200 substances in typical pharma portfolio, there were about 66% of drugs with PDE > 100 ug/day, 36% of drugs with PDE <100 ug/day. In this dataset, there were 12% of substances with PDE <10 ug/day, and 2% of drugs with PDE < 1 ug/day.
In general there are several groups of substances that are already considered HPAPI based on previous criteria, such as low therapeutic dose (eg., peptide hormone oxytocin, guanylate cyclase stimulant for irritable bowel syndrome, dopamine agonists for Parkinsosn’s disease), or drugs that have adverse effects in low doses (eg. certain genotoxic antineoplastics) or both of these criteria (eg. sex steroids and sex hormone modulators). Table 1 However there are some substances that might have relatively high therapeutic doses, which are not dosed daily (eg. bisphosphonates). These doses must be for the purposes of PDE and OEL calculations extrapolated to daily doses, showing that the therapeutic dose alone is not a good indicator of HPAPI.

Figure 1

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Figure 1
Drugs with their Mode of Action (MoA) that have PDEs lower than 10 ug/day.

Table 1

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Table 1
Adjustment factors (AF) typically used in the derivation of PDE for systemically administered drugs. Multiplication of all AFs is termed Composite Adjustment Factor (CAF). Detailed description of the use of these AFs is described in Novartis Global technical best practice document Calculation of the Permitted Daily Exposure (PDE) for drug substances (DS) and intermediates (IM).


An OEL of 1 ug/m3 is a good indicator that a PDE value will be under 10 ug/day, however daily dose may not be.


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