Maximum Recommended Therapeutic Dose (MRTD) Database

FDA's Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Informatics and Computational Safety Analysis Staff's Maximum Recommended Therapeutic Dose (MRTD) database contains values for 1,220 pharmaceuticals listed in Martindale: The Extra Pharmacopoeia (1973, 1983, and 1993) and The Physicians' Desk Reference (1995 and 1999).

Most of the MRTD values in the database were determined from pharmaceutical clinical trials that employed an oral route of exposure and daily treatments, usually for 3 - 12 months. The pharmaceuticals were given as single or divided dose treatment regimens to achieve desired pharmacological effects. In contrast, roughly 5% of the pharmaceuticals in the MRTD database were antineoplastics and anesthetics and were administered intravenously and/or intramuscularly. When separate MRTDs were reported for different routes of exposure, only the oral MRTD was included in the database. In addition, some pharmaceuticals have different MRTD values for male and female adults, children, or elderly patients. In this situation only MRTD values for the average adult patient were used and are reported here.

Pharmaceuticals that are administered orally are usually tested over a limited range of doses and have MRTDs reported as mg/day. We converted the mg/day unit to mg/kg-body weight (bw)/day based upon an average adult weighing 60 kg. In contrast, the dose unit for most antineoplastic drug MRTDs is reported as mg/m² which was converted to mg/kg-bw/day using the formula mg/kg-bw/day = mg/m²/37 for an average adult. Additionally, a few drugs had MRTDs reported in parts per million (ppm) which were converted to mg/kg-bw/day on the basis that 1000 ppm equals 25 mg/kg-bw/day for an average 60 kg adult. MRTD values for the 1,220 chemicals in this dataset range from 0.00001 to 1000 mg/kg-bw/day.

Some classes of chemicals were excluded from the MRTD database due to their unsuitability for most QSAR modeling programs. These were: inorganic chemicals, high molecular weight polymers (>5000 Daltons), fibers, salts, mixtures of organic chemicals and small molecules (<100 Daltons).

The MRTD database displayed in the table format below contains three fields or columns of  information:

1. Maximum Recommended Therapeutic Dose (MRTD) value for adults expressed in mg/kg-bw/day
2. The generic name of each chemical
3. The chemical structure in Simplified Molecular Input Line Entry System (SMILES) code format (generated using MultiCASE Inc.'s MC4PC program)

All data contained in this file are non-proprietary.

This is the non-proprietary portion of the information on which the research published as "Matthews, E.J., Kruhlak, N.L., Benz, R.D., and Contrera, J.F. Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data, Current Drug Discovery Technologies, 2004, 1:61-76" was based. The abstract for this report is as follows:

The primary objective of this investigation was to develop a QSAR model to estimate the no effect level (NOEL) of chemicals in humans using data derived from pharmaceutical clinical trials and the MCASE software program. We believe that a NOEL model derived from human data provides a more specific estimate of the toxic dose threshold of chemicals in humans compared to current risk assessment models which extrapolate from animals to humans employing multiple uncertainty safety factors. A database of the maximum recommended therapeutic dose (MRTD) of marketed pharmaceuticals was compiled. Chemicals with low MRTDs were classified as high-toxicity compounds; chemicals with high MRTDs were classified as low-toxicity compounds. Two separate training data sets were constructed to identify specific structural alerts associated with high and low toxicity chemicals. A total of 134 decision alerts correlated with toxicity in humans were identified from 1309 training data set chemicals. An internal validation experiment showed that predictions for high- and low-toxicity chemicals were good (positive predictivity >92%) and differences between experimental and predicted MRTDs were small (0.27 - 0.70 log-fold). Furthermore, the model exhibited good coverage (89.9 - 93.6%) for three classes of chemicals (pharmaceuticals, direct food additives, and food contact substances). An additional investigation demonstrated that the maximum tolerated dose (MTD) of chemicals in rodents was poorly correlated with MRTD values in humans (R² = 0.2005, n = 326). Finally, this report discusses experimental factors which influence the accuracy of test chemical predictions, potential applications of the model, and the advantages of this model over those which rely only on results of animal toxicology studies.

More recently, these data were used as the basis of the research published as "Contrera, J.F., Matthews, E.J., Kruhlak, N.L., and Benz, R.D. (2004) Estimating the Safe Starting Dose in Phase I Clinical Trials and No Observed Effect Level Based on QSAR Modeling of the Human Maximum Recommended Daily Dose. Regulatory Toxicology and Pharmacology 40:185-206." The abstract for this article is as follows:

Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clinical trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clinical trials. The MRDD is an estimated upper dose limit beyond which a drug's efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicological) or undesirable pharmacological effects are observed. The NOAEL in test animals is currently used to estimate the safe starting dose in human clinical trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chemicals in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topological descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74–78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of ±10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clinical trials with the addition of a 10-fold safety factor. For non-pharmaceutical chemicals any compound-related effect can be considered an undesirable and adverse toxicological effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.

An enhanced and modified version of this database may be found on the Distributed Structure-Searchable Toxicity (DSSTox) Public Database Network. [external link]

Please send questions or comments concerning the contents of this page to: R.Daniel.Benz@fda.hhs.gov.

Maximum Recommended Therapeutic Dose (MRTD) Database (1,220 pharmaceuticals)

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