With a portfolio of more than 500 clinical studies performed both in healthy volunteers and patients, CROss Alliance® team has built “on the field” a deep knowledge of several clinical areas. An overview of our capabilities in these specific areas is provided here below, but for any additional request, do not hesitate to get in touch with us.
We constantly try to expand this section, so do not forget to come back and check for further updates.
More than 70 different molecules have been tested by CROss Alliance® in bioequivalence (BE) and bioavailability (BA) studies carried out in healthy volunteers for the clinical development of both ethical or generic drugs. In these studies small & high molecular weight compounds, endogenous substances, pro-drugs and locally active drugs were investigated.
Thanks to the in house availability of senior biostatisticians and pharmacokinetic experts, CROSS’ team is able to advice its Clients in the selection of the most suitable BE/BA study design (parallel, cross over, replicated, two-stage) for each molecule considering the specific regulatory framework (EMA / FDA) and maximising the possibility of success.
CROss Alliance clinical team has deep expertise in most administration routes: intravenous (bolus or infusion), subcutaneous, intramuscular, oral, epicutaneous, vaginal and rectal which do not represent an obstacle neither for the performance of the studies nor for the recruiting of subjects. Moreover, all relevant pharmaceutical forms have been tested at CROSS’ clinical unit: solutions, suspensions, capsules, tablets (ODT, IR, MR), granules, films, creams, gels, transdermal plasters or patches and suppositories.
Molecules investigated in clinical BE/BA studies
|Alendronate||EPA / DHA||Melatonin||Propafenone|
The long QT syndrome is a disease of myocardial ion channels that manifests clinically as recurrent syncope or cardiac arrest due to malignant ventricular arrhythmias. Health Authorities issued a specific guideline while protocols satisfying the regulatory demand have been designed.
CROss Alliance® has acquired a specific expertise in QTc prolongation studies performed in HV and in cooperation with ERT (leading provider for cardiac safety), is able to offer a full service QTc prolongation study compliant with the different US and EU regulatory requests.
To learn more about CROSS & ERT cooperation:
1) Rosignoli MT, Di Loreto G, Dionisio P. “Effects of prulifloxacin on cardiac repolarization in healthy subjects: a randomized, crossover, double-blind versus placebo, moxifloxacin-controlled study”. Clin Drug Investing. 2010;30(1):5-14. PubMed
Acquired expertise in HV and/or patients
1. PK in Cerebral Spinal Fluid: When it is unknown whether a drug penetrates the CNS, determination of its presence into the CSF helps in establishing valuable PK/PD relationships. Studies on this nature are difficult to perform for ethical and technical reasons as it is not feasible to collect more than a few samples per subject. Therefore, population based pharmacokinetic approaches describing serum vs. CSF concentrations of the drug, are required, (1).
2. Positron Emission Tomography: A validated approach to obtain data of a NCE at the earlier stage of development is the microdosing concept which involves administration of a sub-pharmacological dose of the test compound to humans. The non invasive nuclear imaging PET in conjunction with 11C or 18F labelling is the method of choice for investigating the kinetic profile of a NCE both in blood and tissues of HV vs. patients administered the labelled drug, (2).
3. Low Resolution Brain Electromagnetic Tomography: With the aim of understanding whether a drug works within the brain, EEG-tomography (LORETA), by combining the high time resolution of the EEG with a source localization method that permits a 3-Dimensional tomography of the brain electrical activity, becomes the technique of choice. Different CNS drugs affect brain structures differently which may be visualized by horizontal, sagittal and coronal slices through the brain regions showing the most significant findings after the drug vs. placebo or by surface-rendered statistical parametric maps, (3).
4. Neuropathic Pain: Phase II studies aimed to treat neuropathic pain have been carried out on NCEs (MAO-B inhibitors and nootropic drugs) administered, according to placebo controlled designs, to patients with neuropathic pain and in HIV patients suffering from antiretroviral treatment induced neuropathy.
1) B. Saletu, P. Anderer, A. Assandri, W. Orazse, M. Abu-Bakr, E. Lindeck-Pozza, G.M. Saletu-Zyhlarz: “Proving central effects of the nutraceutical and supplementary substance S-adenosyl-L-methionine (ademetionine) by pharmaco-EEG mapping”. Textbook of the training course of the 11th Biennial Congress of Pharmaco EEG, Vienna 2000.
2) Saletu B, Anderer P, Linzmayer L, Semlitsch HV, Lindeck-Pozza E, Assandri A, di Padova C, Saletu-Zyhlarz GM. “Pharmacodynamic studies on the central mode of action of S-adenosyl-L-methionine infusions in elderly subjects, utilizing EEG mapping and psychometry”, J Neural Transm 2002 ;109:1505-26. PubMed
3) Saletu-Zyhlarz GM, Anderer P, Linzmayer L, Semlitsch HV, Assandri A, Prause W, Hassan Abu-Bakr M, Lindeck-Pozza E, Saletu B. “Visualizing central effects of S-adenosyl-L-methionine (SAMe), a natural molecule with antidepressant properties, by pharmaco-EEG mapping.” Int J Neuropsychopharmacol 2002 Sep;5(3):199-215. PubMed
4) Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. “Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography.” Am J Clin Nutr. 2002 Nov;76(5):1162S-71S. PubMed
5) Valle M, Barbanoj MJ, Donner A, Izquierdo I, Herranz U, Klein N, Eichler HG, Muller M, Brunner M. “Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers”. Eur J Clin Pharmacol. (2005), 61, 103-11. PubMed
6) Arnold O, Saletu B, Anderer P, Assandri A, di Padova C, Corrado M, Saletu-Zyhlarz GM. “Double-blind, placebo-controlled pharmacodynamic studies with a nutraceutical and a pharmaceutical dose of ademetionine (SAMe) in elderly subjects, utilizing EEG mapping and psychometry”. Eur Neuropsychopharmacol. (2005)15, :533-43. PubMed
7) Bauer M, Langer O, Dal-Bianco P, Karch R, Brunner M, Abrahim A, Lanzenberger R, Hofmann A, Joukhadar C, Carminati P, Ghirardi O, Piovesan P, Forloni G, Corrado ME, Lods N, Dudczak R, Auff E, Kletter K, Muller M. “A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer’s disease”. Clin Pharmacol 2006 80(3):216-27. PubMed
8) Anderer P, Saletu B, Wolzt M, Culic S, Assandri A, Nannipieri F, Rosini S and Saletu-Zyhlarz G.M, “Double-blind, placebo-controlled, multiple-ascending-dose study on the effects of ABIO-08/01, a novel anxiolytic drug, on perception and cognition, utilizing event-related potential mapping and low-resolution brain electromagnetic tomography” Hum. Psychopharmacol. 2008 Apr.23(3):243-54. PubMed
9) Saletu-Zyhlarz GM, Anderer P, Wolzt M, Semlitsch HV, Assandri A, Nessi P, Nannnipieri F, Rosini S, Saletu B “Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Study on the pharmacodynamics of ABIO-08/01, a New CNS Drug with Potential Anxiolytic Activity. 1. EEG Mapping, Psychometric and Tolerability Findings.” Neuropsychobiology. 2009 Apr 10;59(2):100-109. PubMed
10) Saletu B, Anderer P, Wolzt M, Nosiska D, Assandri A, Noseda E, Nannipieri F, Saletu-Zyhlarz GM “Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Study on the Pharmaco-dynamics of ABIO-08/01, a New CNS Drug with Potential Anxiolytic Activity. 2. EEG-Tomography Findings Based on LORETA (Low-Resolution Brain Electromagnetic Tomography)” Neuropsychobiology. 2009 Apr 10;59(2):110-122. PubMed
11) Leuratti C, Sardina M, Ventura P, Assandri A, Müller M, Brunner M., “Disposition and Metabolism of Safinamide, a Novel Drug for Parkinson’s Disease, in Healthy Male Volunteers.” Pharmacology. 2013 Oct; 92:207-16. PubMed
12) Loprete L, Leuratti C, Cattaneo C, Thapar M M, Farrel C, Sardina M, “Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson’s disease”. Pharmacology Research & Perspectives. 2016 Oct; 4. WOL
Acquired expertise in healthy volunteers and/or patients
1. Basic PK studies: The release of a test drug from a topical formulation, its percutaneous absorption, systemic bioavailability and safety are determined in HV and patients administered by single/multiple doses of gels, creams, ointments, foams, plasters, patches, films, etc. The relationships existing between the measured kinetic parameters and the site of application, the skin properties, the environmental conditions, and the patch adhesiveness, can be investigated (1-2).
2. Safety studies: With the aim of assessing the local tolerability & sensitisation potential, dermal irritation, photo-toxicity and photo-sensitisation are performed following protocols as for the relevant guidelines (4).
3. Topical corticosteroids (Cs): Topical Cs exerts vasoconstriction on the peripheral dermal vessels causing skin blanching. The magnitude of this effect is measured using colorimetric techniques and it is accepted as a surrogate variable BA when a Cs-product is applied to the skin. It is then possible to establish the BE between 2 topical products containing the same quali-quantitative composition in Cs and excipients.
4. Percutaneous absorption: In vivo PK data on the penetration into sub-epidermal layers of a test drug is possible by employing microdialysis and 2-D ultrasound. The technique is based on diffusion of analytes from the extra-cellular space through a semi-permeable membrane. The process is accomplished in vivo by a probe perfused with a physiological solution at low flow rate. Once probe is implanted into the tissue, substances diffuse from the extra-cellular fluid into the perfusion medium, which is collected and analysed (3).
5. Skin Biopsy: Androgenetic alopecia depends both on genetic predisposition and on the local presence of androgen dihydrotestosterone (DHT) which is formed from testosterone (T) by a 5-alpha reductase. Patients with androgen insensitivity syndrome and type-2 5-alpha reductase deficiency, show activation of follicular androgen receptors by DHT. In males undergoing a pharmacological treatment with a test drug T and DHT concentrations can be concurrently analysed in scalp biopsies and serum (5-6).
6. Efficacy trials: Study protocols designed to investigate the efficacy of a test drug in patient populations with different dermatological pathologies (acne, alopecia, herpes, psoriasis, atopic dermatitis) have been developed by Cross and can be tailored for other test molecules.
(1) Brunner M, Davies D, Martin W, Leuratti C, Lackner E, Müller M. “A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects.” Br J Clin Pharmacol. 2011 Jan 17. PubMed
(2) Monti D, Herranz U, Dal Bo L, Subissi A. “Nail penetration and predicted mycological efficacy of an innovative hydrosoluble ciclopirox nail lacquer vs. a standard amorolfine lacquer in healthy subjects.” J Eur Acad Dermatol Venereol. 2013 Feb. PubMed
(3) Burian A, Frangione V, Rovati S, Mautone G, Leuratti C, Vaccani A, Crevenna R, Keilani M, Burian B, Brunner M, Zeitlinger M. “An exploratory microdialysis study investigating the effect of repeated application of a diclofenac epolamine medicated plaster on prostaglandin concentrations in skeletal muscle after standardized physical exercise.” Br J Clin Pharmacol. 2013 Apr 1. PubMed
(4) Di Stefano A F D, Radicioni M M, Vele A, Mancarella Eberhardt A, Caccia G, Focanti F, Salvatori E, “Tolerability and hydrating effects of an anti-aging gynaecological collagen cream in women in menopause” OJOG. 2014 Feb; Vol.4, No.3. OJOG
(5) Caserini M, Radicioni M, Leuratti C, Annoni O, Palmieri R, “A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers.” Int J Clin Pharmacol Ther. 2014 Oct; 52(10):842-9. PubMed
(6) Caserini M, Radicioni M, Leuratti C, Terragni E, Iorizzo M, Palmieri R, “Effect of a novel finasteride 0.25% topical solution on scalp and serum dihydrotestosterone in healthy men with androgenetic alopecia”. International Journal of Clinical Pharmacology and Therapeutics. 2016; 54:19-27. PubMed
Acquired expertise in HV and/or patients
1. Effect of gastric pH on drug absorption: pump inhibitors administration allows increasing gastric juice pH that can be continuously recorded by nasal-gastric probes while the rate and extent of the systemic absorption of a test drug is concurrently measured.
2. Gastrolesivity evaluation: NSAIDs alone or in combination administered at high dosages according to multiple regimens induce gastric damages (erosions, submucosal hemorrhages, ulcers) that can be easily monitored and scored by gastric endoscopy, (1).
3. Small intestine damages: the most recent Video Capsule Endoscopy with the PillCam™, is a valuable tool to investigate, throughout the whole gastro intestinal tract but particularly in the non endoscopically accessible small intestine, treatment related events.
4. Pharmaco-scintigraphy: is a technique used to evaluate the in vivo performance of new oral delivery systems, i.e. capsules, tablets, pellets, enemas. When these data are compared with the PK of the drug it is possible to relate the drug absorption to the formulation fate in the GI tract (location, transit, disintegration, persistence). Complex forms, like enteric-coated tablets, can be labelled by the addition of a non-radioactive tracer as 152Sm2O3 followed by neutron activation of the final product, (2, 3).
1) Di Stefano AF, Radicioni MM, Vaccani A, Fransioli A, Longo L, Moro L, Repici A, “Methylene blue MMX® tablets for chromoendoscopy. Bioavailability, colon staining and safety in healthy volunteers undergoing a full colonoscopy”. Contemporary Clinical Trials August 2018. PubMed
2) Radicioni MM, Koirala R, Fiore W, Leuratti C, Guglielmetti S, Arioli S, “Survival of L. casei DG® (Lactobacillus paracasei CNCMI1572) in the gastrointestinal tract of a healthy paediatric population”. European Journal of Nutrition. November 2018. Springer
3) Seng Yue C1, Benvenga S, Scarsi C, Loprete L, Ducharme MP, “When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets”. J Pharm Pharm Sci. 2015 Dec; 18:844-55. PubMed
4) Travis S P L, Danese S, Kupcinskas L, Alexeeva O, D’Haens G, Gibson P R, Moro L, Jones R, Ballard E D, Masure J, Rossini M, Sandborn W J, “Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study.” Gut. 2014; 63:433-441. Gut
5) A.F.D. Di Stefano, D. Binelli, W. Labuschagne, M. Mojapelo, E. van der Walt, S. Patel and L. Moro “Efficacy of the Treatment of Infectious Diarrhoea with Non-Absorbable Rifamycin SV Formulated as MMX Modified Release Tablet vs. Rifaximin” Anti-Infective Agents, 2013, vol.11, 192-203 Bentham Science
6) A. Repici, A.F.D. Di Stefano, M.M. Radicioni, V. Jas, L. Moro, S. Danese “Methylene blue MMX® tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers” Contemporary Clinical Trials 2012 Mar; 33:260-267. ScienceDirect
7) Di Stefano AF, Rusca A, Loprete L, Dröge MJ, Moro L, Assandri A. “Rifamycin SV systemic absorption in healthy volunteers administered as modified release MMX(R) tablets”. Antimicrob Agents Chemother. 2011 May; 55:2122-2128. PubMed
8) G.R. D’Haens, Á. Kovács, P. Vergauwe, F. Nagy, T. Molnár, Y. Bouhnik, W. Weiss, H. Brunner, A. Lavergne-Slove, D. Binelli, A.F.D. Di Stefano and P. Marteau. Clinical trial: “Preliminary efficacy and safety study of a new Budesonide-MMX® 9 mg extended-release tablets in patients with active left-sided ulcerative colitis”. Journal of Crohn’s and Colitis Volume 4, Issue 2, June 2010, Pages 153-160. PubMed
9) Brunner M, Ziegler S, Di Stefano AF, Dehghanyar P, Kletter K, Tschurlovits M, Villa R, Bozzella R, Celasco G, Moro L, Rusca A, Dudczak R, Muller M. “Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation”. Br J Clin Pharmacol. (2005) ,61, 31-38. PubMed
10) Brunner M, Assandri R, Kletter K, Tschurlovits M, Corrado ME, Villa R, Eichler HG, Muller M. “Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation”. Aliment Pharmacol Ther. (2003). 17, 395-402. PubMed
11) Fiorucci S, Santucci L, Gresele P, Faccino RM, Del Soldato P, Morelli A. Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology. 2003 Mar;124(3):600-7. PubMed