Differences In Bioequivalence Research Articles

Pharmacokinetics of prednisolone in children: an open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease

IntroductionOne in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat...

에스오메프라졸 마그네슘 이수화물을 함유하는 장용성 제제의 안정성 개선

Omeprazole, a benzimidazole derivative, suppresses gastric acid secretion by inhibiting H+/K+ ATPase in gastric parietals cells, and by reducing H+ concentration. To improve stability of esomeprazole magnesium dihydrate (ESMD), enteric-coated preperation was composed of core tablet, subcoating and enteric coating layer. We were evaluated in vitro dissolution characteristics between test and reference ESMD preparation and stability. We could prepare enteric-coated formulation of ESMD by controlling disintegrating agent and coating ratio which could rapidly dissolved in neutral or alkali medium. The formulation D5 with crospovidone of 1.25% and coating ratio of 16.25% had a similar dissolution behavior compare to reference preparation. Difference factor (f1) and similarity factor (f2) were 0~15 and 50~100 and there was no significant difference in bioequivalence between formulations. The content and dissolution rate of formulation D5 were 96.54±0.21 and 78.56±0.87% without change of color in accelerated condition (40oC, RH 75%, high density polyethylene(HDPE) container) for 6 months. This study concluded that our enteric coated preparation of ESMD could be an useful method to improve stability of unstable drug without direct contact with coating material.

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting

PurposeThe therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. MethodsA prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4±16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. ResultsPatients had epilepsy for a mean period of 14.1±10.6years and the mean daily LEV dose was 2583.3±763.7mg. The mean AUC±SD and Cmax±SD was 288.4±86.3(mg/L)h and 37.8±10.4mg/L respectively for brand LEV and 319.2±104.7(mg/L)h and 41.6±12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. ConclusionsIn our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV.

The Glucosamine Controversy; A Pharmacokinetic Issue

Glucosamine (GlcN) is a naturally occurring aminosugar that is widely used to treat osteoarthritis despite controversial clinical trial results. Animal studies, on the other hand, unequivocally suggest anti-inflammatory and disease modifying effects for GlcN. Many explanations have been offered as to the root of the controversy. They include superiority of a crystalline sulphate salt over HCl, industry bias, insensitive assessment metrics and poor methodology. Herein, we rule out a difference in bioequivalence between GlcN salts and that of chemically equivalent doses and suggest additional factors; i.e., inconsistency in the chemical potency of some products used, under-dosing of patients as well as variable and erratic bioavailability indices for the lack of GlcN efficacy observed in some studies. Clinical trials using higher doses of pharmaceutical grade GlcN or formulations with greater bioavailability should yield positive results.

Extensive elevation of creatine kinase with generic clozapine, but not with Leponex

Mr. M., a 27-year-old man, was hospitalized due to an exacerbation of his paranoid schizophrenia persisting for 8 years. Laboratory tests, a magnetic resonance imaging scan and an electroencephalogram revealed no indication of an organic cause of his recurrent psychotic symptoms. When the patient was earlier treated with several atypical as well as typical antipsychotics, either inadequate symptom control, or multiple adverse effects such as severe sleepiness, extrapyramidal motor side effects and sexual dysfunction were observed. Therefore we decided to treat him with clozapine. At that point, all laboratory results including creatine kinase (CK) (47 U/l) werewithin the normal range. After 5 days of upwardly titrating the dose of a generic manufactured clozapine to 50 mg, an increase of CK up to 1219 U/l was noted in a routine blood test. The patient did not receive concomitant medication. The increasing CK was not related to trauma or excessive muscle activity. Another blood sample taken 24 h later showed that the CK had risen further to 2763 U/l. Therefore, we stopped the generic clozapine at 50 mg. Despite discontinuation of the treatment with generic clozapine, CK levels continued to increase up to 3644 U/l within the next 2 days. To prevent acute kidney failure, treatment with sodium-chloride infusions 4 l/daywas instituted. The CK tapered off to normal levels over the next 6 days. This was the first time the patient had developed CK elevation while receiving antipsychotic treatment. Suspecting that the increase of CK was due to the generic clozapine and considering the patient's chronicity and earlier resistance to treatment, we decided to start antipsychotic treatment again with clozapine, but this time using Leponex. After upward titration of Leponex to a maximum of 300 mg/day, daily blood samples showed the CK levels to be within normal range. Studies have been examining the differences between Leponex and generic clozapine since the Leponex patent was extended in 1998. Concerning side effects, generic clozapine was not associated with an increase in reported adverse effects compared with Leponex in general. However, several studies showed differences in bioequivalence and interchangeability between Leponex and generic clozapine. Furthermore, it has been reported that these differences in bioequivalence might have consequences for the pharmacokinetic profile that result in a higher maximum plasma concentration leading to increased or emergent adverse effects. CK elevations related to clozapine treatment have been reported several times before. To our knowledge this is the first case in which an adverse effect associated with generic clozapine disappeared after changing the treatment to Leponex. We therefore suggest that due to certain risk factors, such as genetic variety or enzyme dysfunctions, differences in bioequivalence and interchangeability occur. These differences might lead to an individual tolerability and adverse effect profile. If CK elevation is observed during clinical monitoring in treatment with generic clozapine, switching to Leponex treatment might be a satisfactory choice.

질산 이소소르비드가 함유된 서방형 펠렛의 제조 및 용출 특성

Isosorbide dinitrate is an oral assiatant therapy agent of angina pectoris, myocardial infarction and congestive heart failure. The objective of this study was to formulate sustained release containing isosorbide dinitrate and assess their formulation variables. Pellets were prepared by fluid bed process and consist of drug layer and membrane layer. The pellets were coated with ethylcellulose along with of plasticizer such as triacetin and diethyl butylrate. In vitro evaluation study was performed by comparative dissolution test between test and reference isosorbide dinitrate preparation. We could prepare sustained pellets of isosorbide dinitrate by fluid bed process which were reduced process time and had high content. The pellet coated with 1% ethylcellulose and triacetin(l5%) had a similar dissolution behavior compare to reference isosorbide dinitrate preparation controlling initial dissolution and those of dissolution at 30 min were 17.25 and 17.09%, respectively. Difference factor and similarity factor were and and there was no significant difference in bioequivalence between formulations. It might be concluded that our sustained release pellet of isosorbide dinitrate could be an alternatively delivery system to reference drug preparation.

Optimizing Metrics for the Assessment of Bioequivalence Between Topical Drug Products

Stratum corneum tape stripping post-application of a drug product followed by analysis of the active agent in this tissue layer is an approach being seriously considered for the comparative assessment of topical bioavailability. Key issues revolve around how best to perform this experiment and interpret the data. Using previously published results from a comparative study of three 0.025% tretinoin gel products, alternative data analysis approaches are presented that may render the technique more accessible to the evaluation of new and generic topical dosage forms. For the tretinoin gel study, the conclusions for bioequivalence from measurements of drug levels at only one uptake and one clearance time were the same as those from the original study, which required measurements at eight different treatment times. Furthermore, comparisons of drug levels at one uptake and one clearance time discriminated differences in bioequivalence for clearance and uptake, which had previously been missed. Half-life estimates, derived from time course data of drug clearance, can be related to lag time for drug penetration through the SC. This new data analysis demonstrates that comparative bioequivalence might be assessed more easily.

Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy

Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy

P.2.001 The antidepressant withdrawal syndrome: update on SSRIs and venlafaxine

Prevention of the serotonin reuptake inhibitor discontinuation syndrome (SRIDS) is an important issue. The author suggests: (1) serotonin reuptake inhibitors (SRIs) should be used only when they are necessary. Sometimes tablets should be replaced with other treatment modalities; (2) patients should be given the lowest dosage of SRIs possible; (3) patients who have a history of medication noncompliance, who have experienced the discontinuation symptoms in the past, or who have treatment-emergent anxiety are at highest risk for experiencing the SRIDS and need closer monitoring; (4) SRIs should be tapered prior to stoppage; (5) generic drugs are allowed up to a 20% difference in bioequivalence from the brand original. Patients should receive continuity of supply from the dispenser, with no intermanufacturer switching; (6) patients and healthcare professionals should be educated to ensure that SRIs are not stopped abruptly; (7) neonatal SRIDS can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and physician should take this into consideration when making treatment decision.

Prevention of the serotonin reuptake inhibitor discontinuation syndrome

Prevention of the serotonin reuptake inhibitor discontinuation syndrome (SRIDS) is an important issue. The author suggests: (1) serotonin reuptake inhibitors (SRIs) should be used only when they are necessary. Sometimes tablets should be replaced with other treatment modalities; (2) patients should be given the lowest dosage of SRIs possible; (3) patients who have a history of medication noncompliance, who have experienced the discontinuation symptoms in the past, or who have treatment-emergent anxiety are at highest risk for experiencing the SRIDS and need closer monitoring; (4) SRIs should be tapered prior to stoppage; (5) generic drugs are allowed up to a 20% difference in bioequivalence from the brand original. Patients should receive continuity of supply from the dispenser, with no intermanufacturer switching; (6) patients and healthcare professionals should be educated to ensure that SRIs are not stopped abruptly; (7) neonatal SRIDS can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and physician should take this into consideration when making treatment decision.

Is generic prescribing acceptable in epilepsy?

There is considerable debate about the role of generic prescribing for people with epilepsy. The arguments go beyond simple considerations of cost on one hand and the possibility of toxicity or loss of seizure control on the other. The concepts of bioavailability and bioequivalence require further consideration. The measures that are currently used may not apply equally well to all situations. For example, additional measures may be needed for controlled-release preparations and in the other special cases. There is an extensive literature on the bioequivalence of various phenytoin preparations. This anticonvulsant drug is poorly soluble in water, has nonlinear kinetics and has a narrow therapeutic range, implying that problems with bioequivalence are likely to occur. This is borne out by clinical experience. There are a few published investigations on carbamazepine. The systematic studies, on the whole, fail to show major differences in bioequivalence between the various formulations. There is sparse information on the comparison between generic and proprietary formulations of other anticonvulsant drugs. Whatever arguments might be put forward supporting brand name or generic prescribing, there are strong reasons for recommending tight control on the consistency of anticonvulsant drugs, both generic and proprietary. There is also a strong case for ensuring that the physician who signs the prescription remains in control of the situation and that any decisions that the physician makes should be based on accurate and reliable information.

Criteria To Assess in Vivo Performance of Sustained Release Products: Application to Diltiazem Formulations

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zerio to infinity),Cmax(peak plasma concentration), andtmax(time to reachCmax), are suitable to determine the extent and rate of absorption of immediate‐release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained‐release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean residence time),Cmax/AUC, peak occupancy time (POT),tapical(the arithmetic mean of the times associated with the concentrations within 25% ofCmax),Capical(the arithmetic mean of the concentration within 25% ofCmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of theCss(steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC,Cmax, andtmaxwere utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 ± 28% and 90 ± 24%, respectively. The 90% confidence intervals (CI) over a mean AUC ratio of 89% were 78–101% (single dose, SD) and 77‐−101% (multiple dose, MD). Following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% CI over a meanCmaxratio of 100% were 83–115% (SD) and 86–115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 ± 37% with a 90% CI of 80–114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameters. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC andCmaxratio, the 90% CIs associated with the ratio of the proposed criteria, with the exception ofCapical, did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parametersCmaxandtmaxfor rate of absorption assessment, their utility in bioequivalence evaluation would require further examination.

Differences in bioequivalence

Differences in bioequivalence

Increased Seizure Frequency With Generic Primidone

GENERIC drugs produced by different pharmaceutical companies may have different rates of extent of absorption.1-8This is particularly important to epileptic patients, because most of the antiepileptic medications have low therapeutic indexes. If a patient switches from an antiepileptic preparation with fairly complete absorption to one with less complete absorption, then the serum drug concentration may drop and the patient could have an increased frequency of seizures. If a patient is switched in the other direction, from a less well-absorbed preparation to one that is better absorbed, then the serum concentrations may rise and the patient could have symptoms of toxic effects. Even if the new product has the same completeness of absorption, there may still be a faster or slower rate of absorption that could affect dosing schedules. These problems have occurred for patients with epilepsy. Previous reports have shown differences in bioequivalence for preparations of phenytoin sodium

Indications and guidelines for plasma tricyclic antidepressant concentration monitoring.

Some tricyclic antidepressants appear to have critical ranges of plasma tricyclic antidepressant concentrations necessary for optimal clinical efficacy. For any given dose of tricyclic medication, there are marked interindividual variations in steady-state tricyclic concentrations. Furthermore, plasma tricyclic concentrations may be influenced by factors such as weight, diet, smoking status, differences in bioequivalence among manufacturers, and the addition or withdrawal of concurrent medications. There has been considerable controversy in the literature about the clinical utility of plasma tricyclic level monitoring. These authors believe that, at present, routine plasma level monitoring probably is not warranted, but that there are a variety of instances where plasma tricyclic concentration determinations may be clinically useful. The authors review methodological issues in plasma tricyclic concentration determinations and suggest guidelines for when such determinations may be clinically appropriate.