Katharina Erb-Zohar

• MD, Dr. med.
• Clinical Pharmacologist & Safety Expert at clinphase

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control gr...

DDI

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV‐seropositive, allogeneic, hematopoietic stem‐cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P‐glycoprotein. The potential...

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem‐cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme‐specific probe drug midazol...

Purpose A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator’s Brochure (IB) for meaningful risk assessment of early clinical trials. Materials and Methods Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance f...

Purpose: To collect information on unintended drug exposure during pregnancy in early clinical drug development. Materials and methods: Questionnaire mailed in autumn 2015 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey. Results: 53 of the ~ 700 addressees participated in the survey...

*** free download at: https://www.dustri.com/nc/article-response-page.html?artId=16617&doi= *** Purpose: To collect information on the use of integrated protocols in early clinical medicines development. Materials and methods: The questionnaire was mailed in fall 2014 to members of human pharmacology societies in Europe for anonymous responses...

Aim: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/preemptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted vi...

Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of leterm...

Introduction/methods: A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethic...

Aims: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. Methods: This was a Phas...

The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites. In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam...

We compared the peak inspiratory flows (PIF) generated through a novel dry powder inhaler device, the Novolizer (PIF-N), and the Turbuhaler (PIF-T). Forty-six pediatric patients with stable bronchial asthma were randomized in an open-label, multicenter, crossover trial. No drug was administered during the inhalation maneuvers that were spaced by 10...

Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with G...

Introduction: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations...

Bioavailability and bioequivalence studies are essential in the clinical development of medicinal products and the optimization of pharmaceutical forms. Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. In practice, drug concen...

Bioavailability and bioequivalence studies are essential in the clinical development of medicinal products and the optimization of pharmaceutical forms. Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. In practice, drug concen...

The standard approach for phenotyping of the human arylamine N-acetyltransferase 2 (NAT2) uses urinary caffeine metabolite ratios after a caffeine test dose taken in after methylxanthine abstinence. We tested whether these standardization measures were still needed when a more sensitive quantification technique was used. A new liquid chromatography...

There is substantial evidence for a causal relationship between genetic variability of the CYP2D6 gene and changes in the pharmacokinetics of drugs. Therefore, knowledge of single-nucleotide polymorphisms (SNPs) prior to drug administration is highly desired for assisting in the development of individualized pharmacotherapy. We therefore developed...

Our objective was to evaluate whether P-glycoprotein inhibition after quinidine pretreatment results in modified central nervous effects of morphine. Twelve healthy volunteers received 7.5 mg morphine as an intravenous infusion over a 3-hour period. In a randomized, double-blind, 2-way crossover fashion, subjects received either 800 mg quinidine or...

Cetrorelix (CET) is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used to prevent premature ovulation in IVF (in vitro fertilization) procedures. The objective of the present study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the LH suppression and LH surge delay after single doses (SD) and multiple...

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjec...

The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion. Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine. Healthy young (...

The objective of this study was to investigate the effects on the pharmacodynamics and noncompartmental pharmacokinetics after weekly subcutaneous administration of novel formulations of cetrorelix acetate in healthy men. In a randomized parallel-group study, single subcutaneous doses of cetrorelix acetate (concentration: 2.5 mg peptide base/ml) di...

To investigate the pharmacodynamic effects and plasma pharmacokinetics of single subcutaneous doses of cetrorelix acetate in healthy premenopausal women. Phase I clinical research unit. Healthy, premenopausal women aged 19 to 35 years. Single subcutaneous morning doses of cetrorelix acetate (1, 3, or 5 mg peptide base) were investigated in a random...

Purpose: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. Background: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the...

Recent research has shown that congenital nonhemolytic low grade hyperbilirubinemias in patients with Gilbert's syndrome (GS) are linked to mutations in the TATA box upstream of the uridine 5'-diphosphoglucose glucuronosyltransferase (UGT1A1) gene leading to an impaired bilirubin glucuronidation. In routine clinical practice GS patients can, howeve...

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast n...

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast n...

BACKGROUND. Teverelix is a novel synthetic peptidic luteinizing hormone-releasing hormone (LHRH) antagonist. Single subcutaneous morning doses of teverelix acetate (either 0.5, 1, 2, 3, or 5 mg base) were investigated in a randomized, single-blind, placebo-controlled, dose-escalating parallel-group design in healthy men. Six subjects received tever...

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation pr...

The pharmacokinetics and metabolic chiral inversion of the S(+)- and R(-)-enantiomers of tiaprofenic acid (S-TIA, R-TIA) were assessed in vivo in rats, and in addition the biochemistry of inversion was investigated in vitro in rat liver homogenates. Drug enantiomer concentrations in plasma were investigated following administration of S-TIA and R-T...

The aims of this study were to investigate the dose-dependent effects of spinally delivered nociceptin (0.3, 1, 3.3 and 10 nmol) on flinching behaviour in the rat formalin test and whether these effects were influenced by the concomitant systemic administration of naloxone (3 mg/kg, i.p.). The effect of the highest nociceptin dose differed statisti...

The usability of noninvasive methods can be quantified by a formal assessment of empirical quality criteria based on test-theoretical principles. The ACVF Doppler aortoechography is a pulsed dual-beam ultrasound technique with online estimates of cardiac output (CO) based upon the measurement of the mean Doppler shift frequency across the ascending...

Validation of study methods is a prerequisite for their usability. Empirical quality criteria based on test-theoretical principles are useful for this purpose. These criteria are discussed for several noninvasive methods used in cardiovascular clinical pharmacology: electrocardiography, systolic time intervals, blood pressure, and estimates of stro...

The cardiovascular responses to various inodilatory interventions were investigated noninvasively in healthy man by monitoring heart rate (HR), blood pressure (SBP/DBP, according to Korotkoff I and IV criteria), systolic time intervals (PEP, VET and QS2) and impedance cardiographic estimates of stroke volume (SV) and cardiac output (CO). The follow...

The motility of lymphatic vessels is regulated by arachidonate metabolites and can, therefore, be altered by cyclooxygenase blockers such as nonsteroidal antiinflammatory drugs (NSAIDs). To investigate the transfer of different NSAIDs via the lymphatic system, pharmacokinetics in plasma and lymph after peroral administration of three model compound...

The purpose of this study was to examine the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the elastic properties of the aorta. A standard diuretic antihypertensive drug, hydrochlorothiazide, served for comparisons. Increased aortic stiffness leads to a reduction of the buffering windkessel function and is a major compo...

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and...

The pharmacodynamic equivalence of a fluorohydrocarbons-(FCH)-free glyceryl trinitrate (GTN, CAS 55-63-0)-containing pump spray with low ethanol content (Nitrolingual-Spray N; TL) versus a conventional FCH-containing GTN spray (Nitrolingual-Spray, R) as reference and a FCH-free GTN pump spray with high ethanol content (TH) was investigated by digit...

Several studies were performed to evaluate the degree of inhibition of angiotensin-converting enzyme (ACE) by an ACE inhibitor by assessing the blood pressure response to a continuous i.v. infusion of increasing doses of angiotensin I in healthy volunteers. We assessed pharmacokinetic and pharmacodynamic interactions of the ACE inhibitor cilazapril...

Die kardiovaskuläre Humanpharmakologie untersucht arzneimittelbedingte Herzkreislaufeffekte am gesunden Menschen, wobei sie Wirkungen feststellt und beschreibt bzw. ausschließt oder die Kreislaufdynamik als Modell anwendet, um Wirkmechanismen von Arzneistoffen zu untersuchen. Dabei ist zu beachten, daß in der Regel unblutige Methoden verwendet werd...

Evaluation of Pharmacodynamic Equivalence of Glyceryl Trinitrate Sprays for Oral Application with or without Fluorochlorohydrocarbons. The pharmacodynamic equivalence of a fluorochlorohydrocarbons(FCH)-free vs a FCH-containing glyceryl trinitrate (NTG, CAS 55-63-0) spray was investigated. Three oral sprays were administered at 24 h intervals to 9 m...

We evaluated the degree of inhibition of angiotensin converting enzyme (ACE), principally by cilazapril, by assessing the blood pressure response to a continuous infusion of increasing doses of angiotensin I, and assessed the possible pharmacokinetic and pharmacodynamic interactions between cilazapril and propranolol in healthy volunteers and patie...

This study compared cardiac stroke volumes using four noninvasive techniques in healthy volunteers: dual-beam Doppler echoaortography, electrical impedance cardiography, mechanosphygmography and M mode echocardiography of the left ventricle. Variations in stroke volume were induced by intravenous atropine in increasing doses and venous tourniquets...

The efficacy of three antihypertensive treatments given for 3 weeks each, 2.5 mg cilazapril, a new potent long-acting angiotensin-converting enzyme (ACE) inhibitor, 120 mg propranolol, and the combination of both, were compared in 17 patients suffering from essential hypertension. Blood pressure control (i.e. sitting diastolic blood pressure at res...

This study compared the antihypertensive effects and the haemodynamic mechanisms of action of an angiotensin converting enzyme (ACE) inhibitor, a beta-blocker and the combination of both in patients with mild to severe hypertension. After a placebo run-in period of 2 weeks, patients were treated for 3 weeks with each of the following: cilazapril (2...

1. The purpose of the present studies was to compare the pharmacodynamic profile of the new ACE inhibitor cilazapril with the beta-adrenoceptor antagonist propranolol in healthy subjects and in hypertensive patients. 2. Hormonal and haemodynamic responses at rest and after pharmacological interventions with angiotensin I and isoprenaline were inves...

1. Six healthy subjects received cilazapril (2.5 mg once daily), propranolol (120 mg once daily), the combination of both and placebo for a period of 1 week each (wash-out phase 1 week). 2. Propranolol and cilazapril reduced systolic and diastolic blood pressure (BP) by 7 mm Hg at peak when compared with placebo. However after the combination, this...

Background: The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion.Objective: Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retig...