The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference.

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor - to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.

Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report.

The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.

Adjusted indirect treatment comparison of the bioavailability of WHO-prequalified first-line generic antituberculosis medicines.

Approval of generic medicines is based on bioequivalence with the innovator product, but it is not unusual for generics to be interchanged with each other. This study investigated the differences in bioavailability between World Health Organization-prequalified antituberculosis generics by means of indirect comparisons to ensure interchangeability between these diverse generics. Data on 22 products containing isoniazid, rifampicin, pyrazinamide, or ethambutol in single- or fixed-dose combination were included. The indirect comparison between generics shows that the differences, expressed as 90% confidence intervals, are always less than 30%. Furthermore, assurances regarding interchangeability of two generic products are reduced when either the point estimate ratios in the original studies are shifted from unity by more than 5% or when the width of the 90% confidence interval is large. From a bioequivalence perspective, not only are the generics bioequivalent with the reference but also all these generics can be interchanged without safety/efficacy concerns.

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

Quantification of BNP7787 (dimesna) and its metabolite mesna in human plasma and urine by high-performance liquid chromatography with electrochemical detection.

A sensitive and accurate assay was developed and validated to determine BNP7787 (dimesna), a new protector against cisplatin-induced toxicities, and its metabolite mesna in plasma and urine of patients. Both analytes were measured as mesna in deproteinized plasma or in urine diluted with mobile phase using high-performance liquid chromatography with an electrochemical detector provided with a wall-jet gold electrode. The assays for BNP7787 and mesna in deproteinized plasma were linear over the range of 1.6-500 microM and 0.63-320 microM, respectively. In plasma, the mean recovery of BNP7787 over the whole concentration range was 100.6% and of mesna 94.6%. The lower limits of quantitation (LLQs) of BNP7787 and mesna in deproteinized plasma were 1.6 microM and 0.63 microM, respectively. For both compounds the within- and between-day accuracy and precision of the assay was better than 12%. The assays for BNP7787 and mesna in urine were linear over the range of 0.8-1200 microM and 0.63-250 microM, respectively. In urine, the mean recovery of BNP7787 over the whole concentration range was 94.1% and of mesna 93.1%. The LLQ of BNP7787 in urine was 0.8 microM and of mesna 1.6 microM. The within- and between-day accuracy and precision of the assay for BNP7787 and mesna was lower than 15%. The stability of mesna in urine increased with an increasing concentration of mesna, lower temperature and addition of EDTA (1 g/l) and hydrochloric acid (0.2 M). BNP7787 in urine was stable for at least 24 h at temperatures in the range of -20 degrees C up to 37 degrees C and independent of the concentration. The developed assays are currently applied for samples of patients with solid tumors participating in a phase I trial of BNP7787 in combination with cisplatin.

Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function.

The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplatin in cancer patients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable) platinum, intact lobaplatin, creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable platinum and intact lobaplatin revealed almost identical patterns. The elimination of ultrafilterable platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. The calculated creatinine Cl was linearly correlated with the total body clearance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated well with the creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.

A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors.

Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination of doxorubicin with the cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received PSC at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses given every 12 h. Doxorubicin was given by i.v. push on day 3 of PSC administration, 4 h after the morning dose of PSC. Pharmacokinetic analyses of PSC and doxorubicin were performed. A total of 38 patients received a combination of PSC and doxorubicin, and 27 received doxorubicin alone in the first course. The major toxicity of the combination was hematological and was significantly more severe than that with doxorubicin alone; severe myelosuppression was already observed at the first PSC dose level, which required doxorubicin dose reduction from 50 to 35 mg/m2. At all dose levels of PSC, up to 17.5 mg/kg/day, there were at least two patients with grade 3 or 4 hematological toxicity, which was manageable in less heavily pretreated patients. A further PSC dose escalation was performed to 25 mg/kg/day, together with doxorubicin, at a further reduced dose of 20 mg/m2. At this dose, central nervous system toxicity became the most relevant side effect. The increase of toxicity in the combined treatment was supported by a significant increase of the area under the plasma concentration-time curve to infinity of doxorubicin (54%) and a 10-fold increase of the area under the plasma concentration-time curve to infinity of doxorubicinol. The pharmacological interaction was not dependent on the plasma concentration of PSC. The total body clearance of doxorubicin decreased by 30%. PSC plasma concentrations of >1 microM at the time of doxorubicin administration were, in general, found at a dose of 7.5 mg/kg/day or higher. One patient had a partial response. In conclusion, PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin. However, a marked pharmacological interaction was found between doxorubicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxorubicin dose. Further study of PSC may be warranted, in association with the investigation of P-glycoprotein expression and concentration of drugs in the tumor tissues.

Determination of the two diastereoisomers of lobaplatin (D-19466) in plasma ultrafiltrate of cancer patients with a normal or an impaired kidney or liver function by high-performance liquid chromatography with ultraviolet detection.

Lobaplatin consists of two diastereoisomers, LP-D1 and LP-D2. Being a new cytostatic agent it represents platinum compounds of the third generation and is active in several in vitro tumor models of murine and human origin. To determine the pharmacokinetics of LP-D1 and LP-D2 in cancer patients with and without a normal kidney and liver function, an HPLC procedure was developed and validated. Plasma ultrafiltrate samples were injected into the HPLC system after solid-phase extraction. The standard curves of LP-D1 and LP-D2 in plasma ultrafiltrate were linear over the range 0.071-9.100 and 0.067-8.639 microM, respectively. The recovery from plasma ultrafiltrate was 84% for both diastereoisomers. The within-day accuracy ranged from 98.1 to 100.3% for LP-D1 and from 96.5 to 106% for LP-D2. The between-day accuracy ranged from 99.2 to 101.5% fro LP-D1 and 97.7 to and < or = 6.5% for LP-D2, respectively. For pharmacokinetic purposes the method proved to be sufficiently sensitive, specific and accurate for analysing clinical samples.

Determination of Elsamitrucin (BMY-28090) in plasma and urine by high-performance liquid chromatography with fluorescence detection.

The cytostatic agent Elsamitrucin is a new fermentation product active in a variety of in vivo tumor models of murine and human origin. To determine its pharmacokinetics during the clinical phase I trial, an HPLC procedure was developed and validated. Plasma samples were extracted after addition of the internal standard, i.e. the analog Chartreusin. Urine samples were injected without extraction of the samples. Because of the wide concentration range of Elsamitrucin in the plasma samples two standard curves were used: up to 100 nM and from 100-1000 nM. Recoveries of Elsamitrucin from plasma were 87% and 74% for concentrations lower and higher than 100 nM, respectively. The detection limits were 1 nM in plasma and 7.5 nM in urine at a signal-to-noise ratio of 3. The accuracy ranged from 95-107% for plasma and from 96-104% for urine. The within-day precision was < or = 4.8% and < or = 2.8% in plasma and urine, respectively. The between-day precision was < or = 4.4% and < or = 7.1% in plasma and urine, respectively. The method proved to be sufficiently sensitive, specific and accurate for analysis of clinical samples for pharmacokinetic purposes.