Larry F. Lacey

Assessment of dose proportionality : report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party

There are a number of different approaches to the assessment of dose proportionality, but most of these are directed toward hypothesis testing. The analysis of dose proportionality studies, however, requires estimation rather than significance testing in order that the pharmacokinetic and clinical significance of any nonproportionality can be assessed. The methods of statistical analysis of these studies have been reviewed. An empirical model relating the log of the pharmacokinetic parameter linearly to the log of the dose (the “power model”) provides a readily interpreted measure of the degree of nonproportionality. The potential utility of this model has been demonstrated using a number of observed dataseis from different drugs. If there is doubt over the goodness of fit of the power model then analysis of variance (after log transformation), together with pairwise comparisons between doses, provides a suitable alternative approach.

Colonic metabolism of ranitidine: implications for its delivery and absorption

The aim of this study was to assess the in vitro stability of ranitidine to colonic bacteria by utilising a batch culture fermentation system to simulate the conditions of the colon. Three quantities of ranitidine, 100, 200 and 500 mg, in the form of the hydrochloride salt, were introduced into individual 100 ml fermenters consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments were also run in parallel using equivalent drug quantities in buffer medium without the presence of faeces. Samples were removed at pre-determined time intervals over a 24 h period and were subsequently analysed by high-performance liquid chromatography (HPLC) for drug concentration. A selection of the samples removed from the fermenters was also analysed by conventional UV spectroscopy and mass spectrometry. Subsequent to an initial dissolution phase in the fermentation system, a marked decline in ranitidine concentration was noted over time, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted in the control buffer systems. The rate and extent of metabolism was rapid and complete within 12 and 24 h for the 100 mg and 200 mg samples, respectively, although the largest sample size, 500 mg, was only partly metabolised over the course of the experiment. UV and mass spectrometry analysis indicated that metabolism occurred via cleavage of an N-oxide bond within the molecule with the resultant loss of an oxygen atom, although further metabolic reactions are possible. Such metabolism may in part be responsible for the poor bioavailability of ranitidine from the colon.

The Effect of Polyethylene Glycol 400 on Gastrointestinal Transit: Implications for the Formulation of Poorly-Water Soluble Drugs

AbstractPurpose. To assess the effect of polyethylene glycol 400 (PEG 400), a pharmaceutical excipient frequently employed to enhance the solubility and bioavailability of poorly water-soluble drugs, on the gastrointestinal transit of liquid and pellet preparations in human subjects using gamma scintigraphy. Methods. Ten, healthy male volunteers each received, on separate occasions, a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). Non-disintegrating pellets of size 1.4-1.7 mm, encapsulated within a hard gelatin capsule, were simultaneously administered on both occasions to act as a marker for solid dosage form transit. The liquid and pellet preparations were radiolabelled with 111In and 99mTc respectively thus enabling their positions within the gastrointestinal tract to be followed using a gamma camera. Results. Rapid liquid emptying from the stomach was observed, with no significant difference noted in the gastric residence times of the two preparations. Caecum arrival times for the liquid preparations were significantly different by virtue of their differential rates of transit through the small intestine. The mean small intestinal liquid transit time for the control preparation was 236 min whereas the corresponding value for the PEG 400-containing test preparation was 153 min. This 35% reduction in transit time was attributed to the presence of PEG 400. Pellet transit was largely unaffected by the presence of PEG 400. Conclusions. These findings clearly demonstrate that PEG 400 has a marked accelerating effect on small intestinal liquid transit, which in turn has implications for the formulation of poorly water-soluble drugs with PEG 400.

Influence of Polyethylene Glycol 400 on the Gastrointestinal Absorption of Ranitidine

AbstractPurpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and Cmax parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.

Formulation of Ranitidine Pellets by Extrusion-Spheronization with Little or No Microcrystalline Cellulose

The present study was concerned with the feasibility of formulating ranitidine into pellets with a range of alternative excipients in place of microcrystalline cellulose (MCC). Eight ranitidine formulations employing two or more of the excipients lactose, barium sulfate, glyceryl monostearate, and MCC were processed by extrusion-spheronization, and characterized according to a series of physico-mechanical and dissolution criteria. Formulations containing lactose produced unsatisfactory pellets of wide size distribution and irregular shape, whereas formulations incorporating barium sulfate and glyceryl monostearate with or without MCC resulted in relatively spherical pellets of narrow size distribution and good mechanical properties. Ranitidine release was found to be rapid and virtually complete within 15 min, regardless of the pellet formulation. A direct relationship was observed between the concentration of MCC in the formulation and the properties of the pellets. In general, the higher the concentration of MCC, the rounder, stronger, and less friable the pellets. However, even pellets without MCC were also successfully prepared with a superior size distribution and shape over those with MCC. Overall, these results confirm that ranitidine can be formulated into pellet dosage forms with little or no MCC by the extrusion-spheronization process.

Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora

The H(2)-receptor antagonist ranitidine has previously been shown to be a substrate for colonic bacterial metabolism. The objective of the present study was to assess the in vitro stability of the other H(2)-receptor antagonists, cimetidine, famotidine and nizatidine, to colonic bacteria. One hundred milligrams of each drug were introduced into individual batch culture fermenters (100 ml) consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments, equivalent drug quantities in buffer medium without the presence of faeces, were also run in parallel. Samples were removed at set time intervals over a 24 h period and were subsequently analysed by HPLC. A selection of the samples removed from the fermenters was also subjected to analysis by UV spectroscopy and mass spectrometry. Following an initial dissolution phase in the fermentation system, a marked decline in nizatidine concentration was noted over time with virtually no drug remaining after 12 h, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted for cimetidine or famotidine or for any of the drugs in the control buffer systems. The metabolic reaction pathway for nizatidine was complex, although UV and mass spectrometry analysis indicated that metabolism was initiated via cleavage of an N-oxide bond within the molecule. These results in combination with those obtained from a previous study indicate that of the four commercially available H(2)-receptor antagonists, nizatidine and ranitidine are susceptible to metabolism by colonic bacteria, which in turn has ramifications for drug delivery and absorption.

Evaluation of Different Metrics as Indirect Measures of Rate of Drug Absorption from Extended Release Dosage Forms at Steady-State

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUC) to evaluate extent of absorption and maximum concentration (Cmax) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as Cmax/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state Cmax is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for Cmax and AUC.

Evaluation of different partial AUCs as indirect measures of rate of drug absorption in comparative pharmacokinetic studies

The performance of different partial AUCs, including partial AUC from zero to t(max) of the reference formulation (AUC(r)) and partial AUC from zero to tmax of test or reference formulation, whichever occurs earliest (AUC(e), as indirect measures of rate of absorption have been evaluated using simulated experiments. The performance of these metrics relative to C(max), t(max) and C(max)/AUC(infinity) was further assessed using the results of actual studies involving a Glaxo drug. The normalised metrics AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) have also been evaluated. Our provisional conclusions were: (1) AUC(r)/AUC(infinity) and AUC(e)/AUC(infinity) had greater statistical power than C(max) and the non-normalised partial AUCs at detecting true differences in rate of absorption. Using real data, the performance of AUC(e)/AUC(infinity) was poor, however, the performance of AUC(r)/AUC(infinity) was good; (2) C(max)/AUC(infinity) was more precisely estimated than AUC(r)/AUC(infinity) or AUC(e)/AUC(infinity) and may be a superior metric for assessing absorption rates of highly variable drugs.

Review of economic benefits of treating chronic hepatitis B with lamivudine.

Chronic hepatitis B (CHB) is a major cause of morbidity and mortality worldwide; and as a result imposes a considerable burden on the patient, their family, and society. The disease is a global healthcare problem and has huge implications on economic healthcare expenditure. Approximately 350 million people are chronic carriers of hepatitis B and, of these, one-third is expected to develop complications arising from hepatitis B infection, resulting in cirrhosis, hepatocellular carcinoma (HCC), liver failure, or death.

Glaxo's experience of different absorption rate metrics of immediate release and extended release dosage forms

As indirect measures (metrics) of rate of drug absorption, Cmax is confounded by extent of drug absorption and tmax is a discrete variable, dependent on blood sampling frequency; therefore, there is a need for improved metrics of rate. Building upon the work of Endrenyi et al. (1) and Chen (2), different metrics have been compared using simulated single dose bioequivalence studies of immediate release (IR) dosage forms. Those investigated included: Cmax/AUC∞, partial AUC from zero to tmax of the reference formulation (AUCr), partial AUC from zero to tmax of the test or reference formulation, whichever occurs earliest (AUCe), and the normalized partial AUCs (AUCr/AUC∞, and AUCc/AUC∞, which like Cmax/AUC∞, are not confounded by extent of absorption) (3,4). Importantly, the performance of these metrics was further assessed using the results of several actual pharmacokinetic studies involving IR dosage forms of Glaxo drugs. For extended release (ER) dosage forms, bioequivalence assessments are carried out at steady-state, using metrics such as Cmax and percentage peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. The performance of the different metrics has been compared using simulated experiments of ER dosage forms at steady-state and also using the results of two actual pharmacokinetic studies involving an ER dosage form of a Glaxo drug. The results obtained from the sets of simulated and actual experiments, using IR or ER dosage forms, allowed the following provisional conclusions to be reached: 1. For IR dosage forms, there was considerable difference between the metrics in the magnitudes of effect produced (ie, in their sensitivities), for a given change in the underlying rate of absorption. This would suggest that the same 80-125% bioequivalence guideline may be inappropriate for all the metrics, 2. For IR dosage forms, Cmax/AUC∞ is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent. Also, Cmax/AUC∞ is more statistically powerful than Cmax at detecting differences in rate of absorption when they exist. The normalized partial AUCs are more powerful than Cmax and the nonnormalized AUCs at detecting true differences in rate of absorption. The performance of AUCe/AUC∞ when used with real data was poor, which may imply that it has little practical value; on the other hand the performance of AUCT/AUC∞ was good, 3. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, produced very small magnitudes of effect, for a given change in rate of absorption. Although %PTF gave the largest effect it was also the most imprecisely estimated, making it difficult to comply with the 80-125% guideline, and 4. None of the metrics tested can be considered to provide reliable information about changes in rate of absorption from ER dosage forms under steady-state conditions. More reliable information using these metrics would be expected from single dose studies.