A simple practice guide for dose conversion between animals and human

A simple practice guide for dose conversion between animals and human

March-May 2016 | Anroop B. Nair, Shery Jacob
This review provides a simple practice guide for dose conversion between animals and humans. Understanding dose extrapolation between species is crucial for pharmaceutical researchers. Interspecies allometric scaling is a controversial area in clinical pharmacology. Allometric scaling considers differences in body surface area, which is related to animal weight, when extrapolating doses of therapeutic agents among species. The review outlines basic information on dose translation between species and the estimation of starting doses for clinical trials using allometric scaling. It also briefly describes the method of calculating injection volume for parenteral formulations based on human equivalent dose. The dose by factor method is an empirical approach that uses the no observed adverse effect level (NOAEL) from preclinical toxicological studies to estimate the human equivalent dose (HED). This method considers the minimum risk of toxicity rather than pharmacologic activity. The similar drug approach uses existing pharmacokinetic data from another drug of the same pharmacological category. The pharmacokinetically guided approach uses drug activity instead of scaling between species. The comparative approach uses various methods to determine the initial dose and compares the data to optimize the initial dose. Allometric scaling is an empirical approach where the exchange of drug dose is based on normalization to body surface area. This method accounts for differences in physiological time among species. The US Food and Drug Administration (FDA) currently uses the dose by factor approach, where the NOAEL is scaled using allometry to derive the maximum recommended starting dose (MRSD) for clinical studies. The MRSD is usually scaled well across animal species when normalized to body surface area (mg/m²). The HED is calculated by converting the NOAEL to HED using the body surface area correction factor (W^0.67). The HED is then divided by a safety factor of 10 to increase the safety of the first human dose. The final step is converting the value to a pharmacologically active dose in humans. The dose by factor method applies an exponent for body surface area (0.67) to convert doses between animals and humans. The HED is calculated using the equation: HED (mg/kg) = Animal NOAEL (mg/kg) × (Weight_animal (kg)/Weight_human (kg))^(1-0.67). For example, if the NOAEL in a rat weighing 150 g is 18 mg/kg, the HED for a 60 kg human is 2.5 mg/kg, resulting in a dose of 150 mg. This HED value is then divided by a factor of 10, resulting in an initial dose of 15 mg. The K_m factor is used to estimate the HED by dividing the average body weight (kg) of the species by its body surface area (m²). The K_m ratio is used to simplify calculations. The HED is calculated using the equation: HED (mg/kg) = AnimalThis review provides a simple practice guide for dose conversion between animals and humans. Understanding dose extrapolation between species is crucial for pharmaceutical researchers. Interspecies allometric scaling is a controversial area in clinical pharmacology. Allometric scaling considers differences in body surface area, which is related to animal weight, when extrapolating doses of therapeutic agents among species. The review outlines basic information on dose translation between species and the estimation of starting doses for clinical trials using allometric scaling. It also briefly describes the method of calculating injection volume for parenteral formulations based on human equivalent dose. The dose by factor method is an empirical approach that uses the no observed adverse effect level (NOAEL) from preclinical toxicological studies to estimate the human equivalent dose (HED). This method considers the minimum risk of toxicity rather than pharmacologic activity. The similar drug approach uses existing pharmacokinetic data from another drug of the same pharmacological category. The pharmacokinetically guided approach uses drug activity instead of scaling between species. The comparative approach uses various methods to determine the initial dose and compares the data to optimize the initial dose. Allometric scaling is an empirical approach where the exchange of drug dose is based on normalization to body surface area. This method accounts for differences in physiological time among species. The US Food and Drug Administration (FDA) currently uses the dose by factor approach, where the NOAEL is scaled using allometry to derive the maximum recommended starting dose (MRSD) for clinical studies. The MRSD is usually scaled well across animal species when normalized to body surface area (mg/m²). The HED is calculated by converting the NOAEL to HED using the body surface area correction factor (W^0.67). The HED is then divided by a safety factor of 10 to increase the safety of the first human dose. The final step is converting the value to a pharmacologically active dose in humans. The dose by factor method applies an exponent for body surface area (0.67) to convert doses between animals and humans. The HED is calculated using the equation: HED (mg/kg) = Animal NOAEL (mg/kg) × (Weight_animal (kg)/Weight_human (kg))^(1-0.67). For example, if the NOAEL in a rat weighing 150 g is 18 mg/kg, the HED for a 60 kg human is 2.5 mg/kg, resulting in a dose of 150 mg. This HED value is then divided by a factor of 10, resulting in an initial dose of 15 mg. The K_m factor is used to estimate the HED by dividing the average body weight (kg) of the species by its body surface area (m²). The K_m ratio is used to simplify calculations. The HED is calculated using the equation: HED (mg/kg) = Animal
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