Search PubMed⌕ Search

Biomedical subjects

I Mahmood

Publications and source records attributed to I Mahmood.

At least 19 recordsLinked to original sources
PubMed2003

Impact of random and fixed (optimal) sampling approach on the Bayesian estimation of clearance.

BACKGROUND AND OBJECTIVE: The population pharmacokinetic approach is based on sparse sampling. In sparse sampling approaches, the selection of the time point(s) is very critical for the prediction of pharmacokinetic parameters. Several investigators have shown that the predictive performance of the Bayesian approach is influenced by the initial estimates of pharmacokinetic parameters as well as the time of blood sampling. The objective of this study is to evaluate the impact of random and fixed sparse sampling approach on the Bayesian estimation of clearance. METHODS: Three drugs were selected for this study. Two sparse sampling methods (random or fixed) using Bayesian approach were used to assess clearance in healthy subjects following a single oral dose. The initial estimates of the model parameters and inter- and intra-subject variabilities were obtained from the previous pharmacokinetic studies conducted in healthy volunteers. The predicted clearance values using sparse sampling (1, 2 or 3 blood samples per subject) were compared with the clearance values obtained by extensive sampling. RESULTS AND CONCLUSION: The results indicated that both random and fixed sampling approaches, irrespective of number of blood samples, can be used to estimate mean population as well as post hoc predicted individual clearance (Bayesian) with accuracy. However, the precision of the prediction of clearance was found to be better with fixed rather random blood sampling approach.

Bayes Theorem↗
PubMed2003

Center specificity in the limited sampling model (LSM): can the LSM developed from healthy subjects be extended to disease states?

BACKGROUND AND OBJECTIVES: Area under the curve (AUC) can be related to the therapeutic or toxic effect of a drug. In order to accurately measure AUC, multiple blood samples are required, but in a clinical setting, frequent blood sampling from the patients is time-consuming and expensive. The limited sampling model (LSM) is one of the approaches that is gaining popularity due to its simplicity for the estimation of AUC using 1 - 3 samples. Despite its simplicity, the LSM has some shortcomings. One of the major drawbacks of the LSM is that the LSM developed under a given condition may not be extended to other conditions. For example, the LSM developed from healthy subjects may not be extended to disease states such as renal or hepatic impairment or vice versa. This characteristic of the LSM can be referred to as "center-specific". In this investigation, the LSM developed from the healthy subjects was used to predict AUC in patients with renal or hepatic impairment. METHODS: Two sets of simulated plasma concentration versus time data for 2 antihypertensive drugs and measured plasma concentration versus time data for 2 representative drugs (A and B) were used in the analysis. RESULTS AND CONCLUSION: The results of the study indicate that the LSM developed from healthy subjects is inadequate to predict AUC in patients with hepatic or renal impairment, indicating center specificity of the LSM.

Antihypertensive Agents↗
PubMed2002

Comparison of different reduced sampling approaches for the estimation of pharmacokinetic parameters for long half-life drugs in patients with renal or hepatic impairment.

OBJECTIVE: To compare 3 different reduced sampling approaches (truncated area, population and Bayesian; sampling schedule till 48 or 72 hours) with the extensive sampling for the estimation of pharmacokinetic parameters for long half-life drugs in healthy subjects and in patients with renal or hepatic impairment. METHODS: Two drugs (extensively metabolized or extensively excreted) whose half-lives were greater than 30 hours were used in this analysis. Pharmacokinetic parameters such as maximum plasma concentration, clearance and half-life were estimated in healthy subjects and in patients using the above-mentioned 3 reduced sampling approaches and then compared with the extensive sampling. RESULTS: The truncated area method failed to detect the same magnitude of difference in pharmacokinetic parameters between healthy subjects and patient populations that was determined using extensive sampling. On the other hand, the population or Bayesian approach provided the same magnitude of difference in pharmacokinetic parameters between the 2 populations that was observed with extensive sampling. CONCLUSION: This study indicates that the truncated area method may be a less suitable method to accurately characterize the pharmacokinetics of a long half-life drug either in healthy subjects or in patients with renal or hepatic impairment compared to a population or Bayesian approach.

Bayes Theorem↗
PubMed2001

Effects of rhizobacteria and root symbionts on the reproduction of Meloidogyne javanica and growth of chickpea.

The effects of rhizobacteria, i.e. Pseudomonas fluorescens, Azotobacter chyroococcum and Azospirillum brasilense, alone and in combination with root symbionts, Rhizobium sp. and Glomus mosseae, on the growth of chickpea, Cicer arietinum, and reproduction of Meloidogyne jaranica were studied. When added alone G. mosseae was better at improving plant growth and reducing galling and nematode reproduction than any other tested organism. Application of P. fluorescens caused an almost similar increase in plant growth to that caused by Rhizobium sp., while use of A. chroococcum was better than A. brasilense in improving growth of nematode --infected plants. Combined use of P. fluorescens with G. mosseae was better at improving plant growth and reducing galling and nematode multiplication than any other combined treatment.

Animals↗
PubMed2001

Application of preclinical data to initiate the modified continual reassessment method for maximum tolerated dose-finding trials.

This study was conducted to evaluate whether the allometric approach can be used to predict maximum tolerated dose (MTD) in humans from animal data. Twenty-five anticancer drugs were taken from the literature and used in this analysis. The results of the study indicate that MTD can be predicted with reasonable accuracy using interspecies scaling. The predicted MTD can then be applied to the modified continual reassessment method retrospectively for the selection of initial and subsequent doses of anticancer drugs in the patient population. This approach can save time and avoid many unnecessary steps to attain MTD in humans if it could be applied prospectively.

Animals↗
PubMed2001

Interspecies scaling: is a priori knowledge of cytochrome p450 isozymes involved in drug metabolism helpful in prediction of clearance in humans from animal data?

The objective of this study was to evaluate whether a priori knowledge of cytochrome P450 isozymes involved in drug metabolism coupled with Mahmood' and Balian's 'rule of exponents' can be helpful for the prediction of clearance in humans using animal data. The clearance of 27 randomly selected drugs metabolized by different isozymes were scaled up from the animal data (at least three animal species) obtained from the literature. Three methods were utilized to generate allometric equations to scale up the clearance values: (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. The results of this study indicate that the knowledge of a particular isozyme does not provide a guide for the failure or success of allometry for the prediction of clearance. There is no trend which indicates that the chances of accurate prediction of clearance for a given drug are comparatively higher or lower when they are metabolized by a particular isozyme.

Administration, Oral↗
PubMed2000

Limited sampling model for the estimation of pharmacokinetic parameters in children.

A limited sampling model (LSM) is proposed for the first-time assessment of pharmacokinetic parameters (area under the concentration-time curve (AUC), Cmax, and T1/2) in children after a single oral dose of drug. Three drugs were evaluated in this study. The LSM was developed for each drug from the data of 10 healthy adult volunteers. The relationship at selected time points between plasma concentration and the AUC or Cmax was evaluated by multiple linear regression. The multiple linear regression that gave the best correlation coefficient (r) for 3 sampling times versus AUC or Cmax was chosen as the LSM. Pharmacokinetic parameters generated using sparse sampling (3 blood samples) were compared with pharmacokinetic parameters generated using extensive sampling (>7 blood samples). The results indicated that a limited sampling model can be developed from adult data to estimate pharmacokinetic parameters in children with fair degree of accuracy.

Administration, Oral↗
PubMed2000

Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods.

The objective of this study was to predict absolute bioavailability in humans from animal data using interspecies scaling as well as indirect approaches. Five different methods were used to predict absolute bioavailability in humans: (i) absolute bioavailability vs body weight (allometric approach); (ii) F = CL(IV)/CL(oral); (iii) F = 1-[CL(IV)/Q]; (iv) F = 1-[CL(oral)/Q]; and (v) F = Q/[Q + CL(oral)]. Methods II-V are indirect approaches, where predicted i.v. or oral clearance and hepatic blood flow (Q) (1500 ml/min) were used to predict absolute bioavailability in humans. Fifteen drugs were tested and the results of this study indicate that all five approaches predict absolute bioavailability with different degrees of accuracy, and are therefore unreliable for the accurate prediction of absolute bioavailability in humans from animal data. In conclusion, although the above-mentioned approaches do not accurately predict absolute bioavailability, a rough estimate of absolute bioavailability is possible using these approaches.

Animals↗
PubMed2000

Interspecies scaling: role of protein binding in the prediction of clearance from animals to humans.

The objective of this study is to evaluate whether unbound clearance of a drug can be predicted more accurately than total clearance using the allometric approach and if there is any real advantage of predicting unbound clearance over total clearance. The total and unbound clearance of 20 randomly selected drugs were scaled up from the animal data (at least three animal species) obtained from the literature. Three methods were used to generate plots to scale up the clearance values: (1) total or unbound clearance versus body weight (simple allometric equation), (2) the product of total or unbound clearance and maximum life span potential (MLP) versus body weight, and (3) the product of total or unbound clearance and brain weight versus body weight. The results of this study indicate that there will be instances when unbound clearance can be predicted better than total clearance or vice versa. In conclusion, unbound clearance cannot be predicted any better than total clearance.

Animals↗
PubMed1999

A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods.

The objective of this study is to compare the empirical allometric approaches with species invariant time methods using equivalent time, kallynochron, apolysichron, and dienetichrons. Pharmacokinetic parameters (clearance, volume of distribution, and elimination half-life) of ethosuximide, cyclosporine and ciprofloxacin were scaled-up from animal data obtained from the literature. Two methods were utilized to generate plots for the prediction of clearance in humans: (i) clearance versus body weight (simple allometric equation); and (ii) the product of clearance and maximum life-span potential (MLP) versus body weight. Plasma concentrations of each of the drugs were predicted using elementary and complex Dedrick plots, equivalent time with an exponent of 0.25 and equivalent time with the exponent obtained from the plot of body weight and half-life. Plasma concentrations of cyclosporine and ciprofloxacin were also predicted by MLP normalization (dienetichrons). Almost similar results in the pharmacokinetic parameters of the tested drugs were obtained by the allometric approach and by the species invariant time methods.

Animals↗
PubMed1999

Allometric issues in drug development.

The concept of correlating pharmacokinetic parameters with body weight from different animal species has become a useful tool in drug development. The allometric approach is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter(s) of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. Over the years, many approaches have been suggested to improve the prediction of these pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Overall, though interspecies scaling requires refinement and better understanding, the approach has lot of potential during the drug development process.

Animals↗
PubMed1999

Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study.

Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.

Animals↗
PubMed1999

The pharmacokinetic principles behind scaling from preclinical results to phase I protocols.

Extrapolation of animal data to assess pharmacokinetic parameters in humans is an important tool in drug development. Allometric scaling has many proponents, and many different approaches and techniques have been proposed to optimise the prediction of pharmacokinetic parameters from animals to humans. The allometric approach is based on the power function Y = aWb, where the bodyweight of the species is plotted against the pharmacokinetic parameter of interest on a log-log scale. Clearance, volume of distribution and elimination half-life are the 3 most frequently extrapolated pharmacokinetic parameters. Clearance is not predicted very well (error between predicted and observed clearance > 30%) using the basic allometric equation in most cases. Thus, several other approaches have been proposed. An early approach was the concept of neoteny, where the clearance is predicted on the basis of species bodyweight and maximum life-span potential. A second approach uses a 2-term power equation based on brain and body weight to predict the intrinsic clearance of drugs that are primarily eliminated by phase I oxidative metabolism. Most recently, the use of the product of brain weight and clearance has been proposed. A literature review reveals different degrees of success of improved prediction with the different methods for various drugs. In a comparative study, the determining factor in selecting a method for prediction of clearance was found to be the value of the exponent. Integration of in vitro data into in vivo clearance to improve the predictive performance of clearance has also been suggested. Although there are proponents of using body surface area instead of bodyweight, no advantage has been noted in this approach. It has also been noted that the unbound clearance of a drug cannot be predicted any better than the total body clearance (CL). In general, there is a good correlation between bodyweight and volume of the central compartment (Vc); hence, Vc does not face the same complications as CL. The relationship between elimination half-life (t 1/2 beta) and bodyweight across species results in poor correlation, most probably because of the hybrid nature of this parameter. When a reasonable prediction of CL and Vc is made, t 1/2 beta may be predicted from the equation t 1/2 beta = 0.693 Vc/CL.

Animals↗
PubMed1999

Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug.

Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a oral dose of buspirone 20 mg, the drug is rapidly absorbed. The mean peak plasma concentration (Cmax) is approximately 2.5 micrograms/L, and the time to reach the peak is under 1 hour. The absolute bioavailability of buspirone is approximately 4%. Buspirone is extensively metabolised. One of the major metabolites of buspirone is 1-pyrimidinylpiperazine (1-PP), which may contribute to the pharmacological activity of buspirone. Buspirone has a volume of distribution of 5.3 L/kg, a systemic clearance of about 1.7 L/h/kg, an elimination half-life of about 2.5 hours and the pharmacokinetics are linear over the dose range 10 to 40 mg. After multiple-dose administration of buspirone 10 mg/day for 9 days, there was no accumulation of either parent compound or metabolite (1-PP). Administration with food increased the Cmax and area under the plasma concentration-time curve (AUC) of buspirone 2-fold. After a single 20 mg dose, the Cmax and AUC increased 2-fold in patients with renal impairment as compared with healthy volunteers. The Cmax and AUC were 15-fold higher for the same dose in patients with hepatic impairment compared with healthy individuals. The half-life of buspirone in patients with hepatic impairment was twice that in healthy individuals. The pharmacokinetics of buspirone were not affected by age or gender. Coadministration of buspirone with verapamil, diltiazem, erythromycin and itraconazole substantially increased the plasma concentration of buspirone, whereas cimetidine and alprazolam had negligible effects. Rifampicin (rifampin) decreased the plasma concentrations of buspirone almost 10-fold.

Aged↗
PubMed1999

A limited sampling approach in bioequivalence studies: application to long half-life drugs and replicate design studies.

OBJECTIVES: The objectives of this study was to develop a limited sampling model (LSM) to predict the area under the curve (AUC) and the maximum plasma concentration (Cmax) for the assessment of bioequivalence studies. METHODS: Two drugs (A and B) were selected for this purpose. Drug A was chosen to test bioequivalence of two formulations with a long half-life (> 35 hours), whereas drug B was chosen to test the bioequivalence of two formulations (half-life = 12 hrs) with a replicate design study. The LSM for both drugs was developed using 5 blood samples each from 15 healthy subjects. The relationship between plasma concentration (independent variable) at selected time points with the AUC or Cmax (dependent variable) was evaluated by multiple linear regression analysis. The multiple linear regression which gave the best correlation coefficient (r) for 5 sampling time vs AUC or Cmax was chosen as the LSM. The predicted AUC and Cmax from the LSM were then used to assess bioequivalence of two different formulations of each drug following a single oral dose. RESULTS: The model provided good estimates of both AUC and Cmax for both drugs. The 90% confidence intervals on log-transformed observed and predicted AUC and Cmax were comparable for both drugs. CONCLUSIONS: The method described here may be used to estimate AUC and Cmax for bioequivalence studies for drugs with long half-lives or for highly variable drugs which may require replicate design studies without detailed blood sampling.

Area Under Curve↗
PubMed1999

Comparison of the Bayesian approach and a limited sampling model for the estimation of AUC and Cmax: a computer simulation analysis.

OBJECTIVES: To compare two limited sampling methods (Bayesian and the limited sampling model) for the estimation of AUC and Cmax following a single oral dose of a hypothetical drug. METHODS: The plasma concentration vs time data sets for 50 subjects using a linear one- or two-compartment pharmacokinetic model were generated by simulation. The limited sampling model (LSM) was developed using samples from 10 subjects using one or two time points. The simulated plasma concentrations were also used for Bayesian evaluation. Bayesian analysis was performed on Non-Mem and mean pharmacokinetic parameters used for simulation were assumed as population pharmacokinetic parameters. In addition a test drug was also used to compare the predicted AUC and Cmax for the two approaches. RESULTS: Both methods were validated in 40 subjects for the hypothetical drug and in 12 subjects for the test drug. Both methods provided good estimates of AUC and Cmax. CONCLUSION: The results indicate that the LSM is similar to the Bayesian method and may be used in lieu of the Bayesian approach in estimating AUC and Cmax using one or two samples in clinical settings without detailed pharmacokinetic studies.

Area Under Curve↗