Loewe additivity

 ( Clinical Pharmacology ) 

In toxicodynamics and pharmacodynamics, Loewe additivity (or dose additivity) is one of several common used for measuring the effects of drug combinations.

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Definition Let $d\_1$ and $d\_2$ be doses of compounds 1 and 2 producing in combination an effect $e$. We denote by $D\_\{e1\}$ and $D\_\{e2\}$ the doses of compounds 1 and 2 required to produce effect $e$ alone (assuming this conditions uniquely define them, i.e. that the individual dose-response functions are bijective). $D\_\{e1\}/D\_\{e2\}$ quantifies the potency of compound 1 relatively to that of compound 2.

$d\_2\; D\_\{e1\}/D\_\{e2\}$ can be interpreted as the dose $d\_2$ of compound 2 converted into the corresponding dose of compound 1 after accounting for difference in potency.

Loewe additivity is defined as the situation where $d\_1\; +\; d\_2\; D\_\{e1\}/D\_\{e2\}\; =\; D\_\{e1\}$ or $d\_1\; /\; D\_\{e1\}\; +\; d\_2/D\_\{e2\}\; =\; 1$.

Geometrically, Loewe additivity is the situation where isoboles are segments joining the points $(D\_\{e1\},0)$ and $(0,D\_\{e2\})$ in the domain $(d\_1,d\_2)$.

If we denote by $f\_1(d\_1)$, $f\_2(d\_2)$ and $f\_\{12\}(d\_1,d\_2)$ the dose-response functions of compound 1, compound 2 and of the mixture respectively, then dose additivity holds when

$\backslash frac\{d\_1\}\{f\_1^\{-1\}(f\_\{12\}(d\_1,d\_2))\}\; +\; \backslash frac\{d\_2\}\{f\_2^\{-1\}(f\_\{12\}(d\_1,d\_2))\}\; =\; 1$

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Testing The Loewe additivity equation provides a prediction of the dose combination eliciting a given effect. Departure from Loewe additivity can be assessed informally by comparing this prediction to observations. This approach is known in toxicology as the model deviation ratio (MDR).

This approach can be rooted in a more formal statistical method with the derivation of approximate with Monte Carlo simulation, as implemented in the R package MDR.

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