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Iftekhar Mahmood

Publications and source records attributed to Iftekhar Mahmood.

15 recordsLinked to original sources
PubMed2006

Prediction of human drug clearance from animal data: application of the rule of exponents and 'fu Corrected Intercept Method' (FCIM).

The objective of this study is to evaluate the predictive performance of the rule of exponents (ROE) and 'fu Corrected Intercept Method' (FCIM) for the human drug clearance. Different classes of drugs such as extensively metabolized, renally excreted, renally secreted, and biliary excreted drugs were used in this analysis. The results of the study indicated that both these methods under given conditions are extremely useful for the prediction of human drug clearance. There are certain situations under which one of these methods is more suited than the other method. Overall, it appears that a rational use of FCIM and the ROE can help a great deal in obtaining a better estimate of the human drug clearance for a wide variety of drugs. The advantages and disadvantages of these two methods are also discussed.

Animals↗
PubMed2006

Prediction of drug clearance in children from adults: a comparison of several allometric methods.

AIMS: In recent years with the advent of paediatric exclusivity and requirements to conduct clinical studies in children, the current emphasis is to find a safe and efficacious dose of a drug in children. It has been suggested that one can predict the clearance of a drug in children according to the equation: CL in the child=adult CLx(weight of the child/70)0.75. Considering the controversy surrounding the exponent of 0.75 for the prediction of clearance and lack of any systematic evaluation of the aforementioned proposal, the objectives of the study were as follows: (i) to determine if indeed the exponent 0.75 is the most suitable exponent for the prediction of clearance in children from adult data; (ii) to explore and search for other exponents that are more accurate or as good as 0.75; and (iii) to propose a new approach (if any) based on the findings of the current evaluation. METHODS: Six methods were used to predict clearance of drugs in children from adult data. Besides evaluating the exponent of 0.75, exponents of 0.80, 0.85 and 1.0 were also evaluated. An empirical approach based on kidney and liver weights was also examined. Based on the results of five methods, a sixth method was introduced. RESULTS: The results of the study indicate that no single method is suitable for all drugs or for all age groups. The exponents 0.75, 0.80, and 0.85 provided the same degree of accuracy or error in the prediction of clearance in children. CONCLUSIONS: Since no single method is suitable for all drugs or for all age groups. A combination of approaches is suggested which may help in improving the prediction of clearance in children from adult data.

Adult↗
PubMed2006

Comments on "a mathematical description of the functionality of correction factors used in allometry for predicting human drug clearance".

In a recent paper, Tang and Mayersohn [(2005) Drug Metab Dispos 33:1294-1296] mathematically described the functionality of the correction factors (CFs), maximum life-span potential (MLP), and brain weight (BrW) used in allometric scaling for the prediction of human drug clearance. They found that there is an intrinsic defect in using correction factors because different combinations of species will produce different prediction results. Analysis with real examples reveals that different predicted clearance values observed with different combinations of animal species, with or without CFs, are not due to the intrinsic defect of the correction factors; rather, it is the effect of the species, observed clearance values in the species, and the range of the body weights. Even if one does not use the CF, the predicted clearance by the simple allometry will still vary by severalfold, depending on the species used in the scaling.

Animals↗
PubMed2005

Interspecies scaling of biliary excreted drugs: a comparison of several methods.

The objective of this study was to evaluate the predictive performance of several methods of interspecies scaling for the prediction of human clearance of drugs which are excreted in the bile. Ten methods of allometric scaling were used to predict human clearance of biliary excreted drugs from animal data. The methods included the simple allometric approach; the rule of exponents; the rule of exponents with a correction factor; the ratio of human and monkey liver blood flow x monkey clearance; product of clearance and bile flow; product of clearance and UDGPT; product of clearance, bile flow, and UDGPT; and a modified version of the last three approaches in association with the rule of exponents. The results of the study indicate that among these ten approaches, the rule of exponents with the correction factor is the best approach for the prediction of human clearance for drugs which are excreted in the bile. The worst approach is the product of clearance, bile flow, and UDGPT. The simple allometry and the monkey liver blood flow (MLBF) approaches gave almost similar results. For some drugs the simple allometry predicted clearance better than the MLBF approach and vice versa.

Administration, Oral↗
PubMed2005

Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins.

With an increasing number of therapeutic proteins moving into preclinical and clinical development, pharmacokinetic factors play an important role in the development of these macromolecules. It is also important that the pharmacokinetic evaluation of these compounds be done as accurately as possible. For macromolecules, evaluation of pharmacokinetic parameters is often complicated by a number of factors. Bioanalytical methods are essential for any pharmacokinetic study, but for many therapeutic proteins the immunoassay and bioassay methodologies are often nonspecific and sometimes the estimation of pharmacokinetic parameters becomes assay dependent. In vivo binding proteins, metabolites and antibody formation may also interfere with bioanalytical methodologies and thus may have significant impact on the pharmacokinetics of therapeutic proteins. There are also difficulties in identifying and quantifying metabolites as well as the binding of therapeutic proteins to endogenous proteins. Some macromolecules exhibit species specificity that complicates the preclinical pharmacological and toxicological evaluation of these compounds. Antibody formation is a particular problem in the preclinical evaluation of therapeutic proteins. Changes in structure or sequence of protein molecules (glycosylation or pegylation) may cause changes in the pharmacokinetics of these compounds. The size of therapeutic proteins may become a hindrance for absorption. Low absorption of intact molecules across biological membranes frequently occurs. Other factors that may affect the pharmacokinetics of a therapeutic protein are immunogenicity, presence of endogenous protein, time of drug administration, and rate and site of drug delivery. The relationship between pharmacokinetics and pharmacodynamics of therapeutic proteins is complex and in most cases is unclear. In many cases the mechanism and site of action are unknown for these compounds.

Absorption↗
PubMed2004

Interspecies scaling of protein drugs: prediction of clearance from animals to humans.

The objective of this study was to evaluate the interspecies scaling for therapeutic protein drugs to predict the systemic clearance in humans from animal data. This study was undertaken to examine whether the rule of exponents of Mahmood and Balian for the prediction of clearance of nonprotein drugs can also be extended to macromolecules. Three different methods were used to predict clearance in humans: (1). clearance versus body weight (simple allometry), (2). the product of clearance and maximum life-span potential (MLP) versus body weight, and (3). the product of clearance and brain weight versus body weight. Data from 15 therapeutic proteins were analyzed, and the results indicated that the clearance of protein drugs can be predicted accurately using simple allometry or brain weight depending on the exponents of the simple allometry. Furthermore, these 15 drugs were scaled up using two species and the predicted clearance was compared with the predicted clearance obtained from more than two species. It was found that more than two species are needed for a reliable prediction of clearance.

Animals↗
PubMed2004

Impact of truncated area under the curve on failed bioequivalence studies: a computer simulation analysis.

The common measures used in a bioequivalence study are area under the curve (AUC) and the maximum plasma concentration. Estimation of AUC requires frequent blood samples. For long half-life drugs, sampling for long periods of time may become cumbersome. To resolve this issue some investigators have suggested the use of truncated AUC in bioequivalence studies for long half-life drugs. The suggested length of time for the truncated AUC is 72 hours. Many studies have been conducted to show that truncated AUC till 72 hours is a suitable approach. However, the suitability of truncated AUC for failed bioequivalence study has not been demonstrated. This report of simulated plasma concentration versus time data evaluates the suitability of truncated AUC for failed bioequivalence study of two hypothetical drugs. The results of the study indicate that the truncated approach for the estimation of the AUC for long half-life drugs in bioequivalence studies may be useful but it also increases the probability of accepting drugs as being bioequivalent when they are not.

Area Under Curve↗
PubMed2004

Estimation of absorption rate constant (ka) following oral administration by Wagner-Nelson, Loo-Riegelman, and statistical moments in the presence of a secondary peak.

The objective of this study was to evaluate the performance of Wagner-Nelson, Loo-Reigelman, and statistical moments methods in determining the absorption rate constant(s) in the presence of a secondary peak. These methods were also evaluated when there were two absorption rates without a secondary peak. Different sets of plasma concentration versus time data for a hypothetical drug following one or two compartment models were generated by simulation. The true ka was compared with the ka estimated by Wagner-Nelson, Loo-Riegelman and statistical moments methods. The results of this study indicate that Wagner-Nelson, Loo-Riegelman and statistical moments methods may not be used for the estimation of absorption rate constants in the presence of a secondary peak or when absorption takes place with two absorption rates.

Absorption↗
PubMed2003

Selection of the first-time dose in humans: comparison of different approaches based on interspecies scaling of clearance.

The authors describe four approaches to selecting a safe starting dose for humans in clinical drug trials based on interspecies scaling of clearance. Human clearance was predicted by scaling for 10 example drugs for which animal clearance values were available in the literature. The predicted human clearance values were then used to select the estimated starting dose in humans. These doses were then compared with the actual doses given to humans during clinical trials. All four approaches used to estimate the first-time dose in humans provided values that were within the dose range given to humans from Phases I to III. This work demonstrates that animal pharmacokinetic data can be used to estimate a suitable human starting dose, provided the data have been obtained from a dose that produces no adverse effects.

Algorithms↗
PubMed2002

Interspecies scaling of biliary excreted drugs.

The objective of this study is to predict clearance of drugs in humans from animals which are excreted in the bile. Clearance (CL) of eight drugs known to be excreted in the bile were randomly selected from the literature. Scaling of CL was performed using at least three animal species. Using simple allometry, CL x mean life-span potential (MLP) or CL x brain weight, CLs of studied drugs were predicted in humans. The choice of one of the methods depended on the 'rule of exponents' as described by Mahmood and Balian. A 'correction factor' was calculated by adjusting bile flow rate based on the species body weight (bile flow = mL/day/kg body weight) or liver weight (bile flow = mL/day/kg liver weight). Using the 'rule of exponents' and combining it with the 'correction factor', the CLs of biliary excreted drugs were predicted in humans. Predicted CLs in humans from animals using simple allometry were several times higher for all eight drugs (% error [range] = 46-1703). Using the 'rule of exponents' and combining it with a 'correction factor' as described in this report provided a substantial improvement (% error [range] = 5-91) in the prediction of CL for biliary excreted drugs. The results of this study indicate that the CL of a biliary excreted drug may be overpredicted in humans and by applying the 'correction factor' employed here, the predictability of drug CL in humans from animal data may be significantly improved.

Algorithms↗
PubMed2002

Prediction of clearance in humans from in vitro human liver microsomes and allometric scaling. A comparative study of the two approaches.

The objective of this study was to evaluate whether the predicted clearance of a drug in humans from in vitro human liver microsomes was comparable with the predicted clearance in humans obtained by allometric scaling. Sixteen drugs were randomly selected from the literature and their hepatic clearances were predicted using human liver microsomes. For allometric scaling at least three animal species were used and three methods were utilized to generate allometric equations to predict the clearance in humans: (i) clearance vs body weight (simple allometry); (ii) product of the clearance and maximum life-span potential (MLP) vs body weight; and (iii) the product of clearance and brain weight vs body weight. The choice of one of the methods was based on the 'rule of exponents' as described by Mahmood and Balian /2,3/. The results of this study indicated that the use of human liver microsomes to predict hepatic clearance in humans may not provide reliable predictions. On the other hand, the prediction of clearance in humans using allometric scaling combined with the 'rule of exponents' can provide comparatively better prediction of clearance in humans.

Animals↗
PubMed2002

Selegiline transdermal system Somerset.

Somerset is developing a selegiline transdermal system (STS) for potential use in the treatment of depression. It has also been developed for Alzheimer's disease (AD), Parkinson's disease and attention-deficit hyperactivity disorder (ADHD) [182121], although no development has been reported for AD or ADHD in recent years. Somerset claims the transdermal system could be more effective than the oral formulation of selegiline already marketed [250573]. In May 2001, Somerset filed an NDA with the US FDA for STS for the treatment of depression [410848], however, in March 2002, the company received a 'non-approvable' letter from the FDA requesting additional efficacy data. At this time, Somerset had scheduled a meeting with the FDA to review and clarify their comments [456735]. Selegiline will be co-promoted in the US by Watson, under the terms of a previous agreement [275389].

Administration, Cutaneous↗
PubMedDate not supplied

Interspecies scaling: predicting oral clearance in humans.

The objective of this study was to test the interspecies scaling approach for a wide variety of drugs to predict oral clearance in humans from animal data. This study is an attempt to evaluate whether the rule of exponents of Mahmood and Balian for the prediction of systemic clearance can also be applied for the prediction of oral clearance in humans. Three different methods were used to generate log-log plots to scale up the clearance values: (1) clearance versus body weight (simple allometric equation), (2) the product of clearance and maximum life-span potential (MLP) versus body weight, and (3) the product of clearance and brain weight versus body weight. Data from 32 drugs were analyzed, and it was concluded that the oral clearance of drugs could be best predicted using one of the allometric equations.

Administration, Oral↗
PubMedDate not supplied

A Bayesian approach for the estimation of pharmacokinetic parameters in children.

A Bayesian method is proposed for the first-time assessment of pharmacokinetic parameters (area under the curve [AUC], maximum concentration [C(max)], half-life [T(1/2)]) in children after a single oral dose. Pharmacokinetic parameters were compared using sparse sampling (three blood samples) with extensive sampling (nine blood samples). Two different therapeutic classes of drugs were evaluated in this study. The population pharmacokinetic parameters and the blood sampling time points were obtained from adult data. The results indicate that the Bayesian approach can be used to estimate pharmacokinetic parameters in children with fair degree of accuracy. The Bayesian method described here can be used to assess pharmacokinetic parameters in children, provided there is a prior knowledge of the pharmacokinetics of a drug in adult population.

Administration, Oral↗