Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin

Zoe Oesterreicher, Sabine Eberl, Beatrix Wulkersdorfer, Peter Matzneller, Claudia Eder, Esther van Duijn, Wouter H J Vaes, Birgit Reiter, Thomas Stimpfl, Walter Jäger, Alina Nussbaumer-Proell, Daniela Marhofer, Peter Marhofer, Oliver Langer, Markus Zeitlinger, Zoe Oesterreicher, Sabine Eberl, Beatrix Wulkersdorfer, Peter Matzneller, Claudia Eder, Esther van Duijn, Wouter H J Vaes, Birgit Reiter, Thomas Stimpfl, Walter Jäger, Alina Nussbaumer-Proell, Daniela Marhofer, Peter Marhofer, Oliver Langer, Markus Zeitlinger

Abstract

Background and objective: In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.

Methods: Healthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography-tandem mass spectrometry.

Results: The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration-time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration-time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration-time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin.

Conclusions: Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies.

Clinical trial registration: ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).

Conflict of interest statement

The authors declared no competing interests for this work.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Concentration–time curves (mean ± standard deviation) of therapeutic-dose ciprofloxacin (400 mg given intravenously over 1 hour, quantified with liquid chromatography–tandem mass spectrometry, cohort A) in plasma (n = 9, filled circles), subcutaneous tissue (n = 8, open triangles), and epithelial lining fluid (ELF, open squares). Note that ciprofloxacin concentrations in ELF were determined only at one timepoint per subject and concentration–time curves represent an average of three subjects per timepoint
Fig. 2
Fig. 2
Dose-adjusted concentration–time curves (mean ± standard deviation) of therapeutic-dose ciprofloxacin (quantified with liquid chromatography–tandem mass spectrometry, cohort A) and microdose ciprofloxacin (quantified with accelerator mass spectrometry, cohort A and cohort B) in a plasma, b subcutaneous tissue, and c epithelial lining fluid. To enable comparison of therapeutic-dose and microdose ciprofloxacin concentrations, values were normalized to the administered dose and expressed as pg equivalents per mL. Note that both microdose and therapeutic-dose ciprofloxacin concentrations in epithelial lining fluid and microdose ciprofloxacin concentrations in plasma were determined only at one timepoint per subject and concentration–time curves represent an average of three subjects per timepoint
Fig. 3
Fig. 3
Correlations of dose-adjusted microdose ciprofloxacin concentrations determined with accelerator mass spectrometry and dose-adjusted therapeutic-dose ciprofloxacin concentrations quantified with liquid chromatography–tandem mass spectrometry in a plasma, b subcutaneous tissue, and c epithelial lining fluid in subjects of cohort A (r Pearson’s coefficient of correlation). To enable comparison of therapeutic-dose and microdose ciprofloxacin concentrations, values were normalized to the administered dose and expressed as pg equivalents per mL

References

    1. O'Neill J. Securing new drugs for future generations: the pipeline of antibiotics. Review on antimicrobial resistance. 2015. .
    1. Burt T, Young G, Lee W, Kusuhara H, Langer O, Rowland M, et al. Phase 0/microdosing approaches: time for mainstream application in drug development? Nat Rev Drug Discov. 2020;19(11):801–818. doi: 10.1038/s41573-020-0080-x.
    1. Lappin G, Noveck R, Burt T. Microdosing and drug development: past, present and future. Expert Opin Drug Metab Toxicol. 2013;9(7):817–834. doi: 10.1517/17425255.2013.786042.
    1. Burt T, John CS, Ruckle JL, Vuong LT. Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans: a practical guide. Expert Opin Drug Deliv. 2017;14(5):657–672. doi: 10.1080/17425247.2016.1227786.
    1. US Food and Drug Administration. Guidance for industry, investigators, and reviewers. Exploratory IND studies. 2006. . Accessed 13 Nov 2021.
    1. ICH Expert Working Group. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2). 2009. Geneva, Switzerland.
    1. Yamane N, Igarashi A, Kusama M, Maeda K, Ikeda T, Sugiyama Y. Cost-effectiveness analysis of microdose clinical trials in drug development. Drug Metab Pharmacokinet. 2013;28(3):187–195. doi: 10.2133/dmpk.DMPK-12-RG-044.
    1. Müller M. Science, medicine, and the future: microdialysis. BMJ. 2002;324(7337):588–591. doi: 10.1136/bmj.324.7337.588.
    1. Chaurasia CS, Müller M, Bashaw ED, Benfeldt E, Bolinder J, Bullock R, et al. AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res. 2007;24(5):1014–1025. doi: 10.1007/s11095-006-9206-z.
    1. Hosmann A, Ritscher LC, Burgmann H, Oesterreicher Z, Jäger W, Poschner S, et al. Concentrations of cefuroxime in brain tissue of neurointensive care patients. Antimicrob Agents Chemother. 2018;62(2):e02164–e2217. doi: 10.1128/AAC.02164-17.
    1. Blakeley JO, Olson J, Grossman SA, He X, Weingart J, Supko JG, et al. Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study. J Neurooncol. 2009;91(1):51–58. doi: 10.1007/s11060-008-9678-2.
    1. Zeitlinger M, Schwameis R, Burian A, Burian B, Matzneller P, Müller M, et al. Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid. J Antimicrob Chemother. 2016;71(4):1022–1026. doi: 10.1093/jac/dkv442.
    1. Ullah S, Matzneller P, Zeitlinger M, Fuhr U, Taubert M. A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(9):1097–1106. doi: 10.1007/s00210-019-01647-w.
    1. Simon P, Petroff D, Dorn C, Ehmann L, Kloft C, Prettin C, et al. Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients: a prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial. Contemp Clin Trials Commun. 2019;15:100375. doi: 10.1016/j.conctc.2019.100375.
    1. Nowak H, Weidemann C, Martini S, Oesterreicher ZA, Dorn C, Adamzik M, et al. Repeated determination of moxifloxacin concentrations in interstitial space fluid of muscle and subcutis in septic patients. J Antimicrob Chemother. 2019;74(9):2681–2689. doi: 10.1093/jac/dkz259.
    1. Matzneller P, Osterreicher Z, Reiter B, Lackner E, Stimpfl T, Zeitlinger M. Tissue pharmacokinetics of telavancin in healthy volunteers: a microdialysis study. J Antimicrob Chemother. 2016;71(11):3179–3184. doi: 10.1093/jac/dkw269.
    1. Matzneller P, Lackner E, Lagler H, Wulkersdorfer B, Osterreicher Z, Zeitlinger M. Single- and repeated-dose pharmacokinetics of ceftaroline in plasma and soft tissues of healthy volunteers for two different dosing regimens of ceftaroline fosamil. Antimicrob Agents Chemother. 2016;60(6):3617–3625. doi: 10.1128/AAC.00097-16.
    1. Burian B, Zeitlinger M, Donath O, Reznicek G, Sauermann R. Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers. Antimicrob Agents Chemother. 2012;56(1):532–535. doi: 10.1128/AAC.05506-11.
    1. Zeitlinger M, Müller M, Joukhadar C. Lung microdialysis: a powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review) AAPS J. 2005;7(3):E600–E608. doi: 10.1208/aapsj070362.
    1. Schwameis R, Zeitlinger M. Methods to measure target site penetration of antibiotics in critically ill patients. Curr Clin Pharmacol. 2013;8(1):46–58.
    1. Rodvold KA, Gotfried MH, Chugh R, Gupta M, Patel A, Chavan R, et al. Plasma and intrapulmonary concentrations of cefepime and zidebactam following intravenous administration of WCK 5222 to healthy adult subjects. Antimicrob Agents Chemother. 2018;62(8):e00682–e718. doi: 10.1128/AAC.00682-18.
    1. Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019;74(7):1971–1974. doi: 10.1093/jac/dkz123.
    1. Brunner M, Langer O, Dobrozemsky G, Müller U, Zeitlinger M, Mitterhauser M, et al. [18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans. Antimicrob Agents Chemother. 2004;48(10):3850–3857. doi: 10.1128/AAC.48.10.3850-3857.2004.
    1. Ordonez AA, Wang H, Magombedze G, Ruiz-Bedoya CA, Srivastava S, Chen A, et al. Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions. Nat Med. 2020;26(4):529–534. doi: 10.1038/s41591-020-0770-2.
    1. Wagner CC, Langer O. Approaches using molecular imaging technology: use of PET in clinical microdose studies. Adv Drug Deliv Rev. 2011;63:539–546. doi: 10.1016/j.addr.2010.09.011.
    1. Bauer M, Wagner CC, Langer O. Microdosing studies in humans: the role of positron emission tomography. Drugs R D. 2008;9(2):73–81. doi: 10.2165/00126839-200809020-00002.
    1. Langer O, Karch R, Müller U, Dobrozemsky G, Abrahim A, Zeitlinger M, et al. Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans. J Nucl Med. 2005;46(11):1835–1841.
    1. Brunner M, Stabeta H, Moller JG, Schrolnberger C, Erovic B, Hollenstein U, et al. Target site concentrations of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 2002;46(12):3724–3730. doi: 10.1128/AAC.46.12.3724-3730.2002.
    1. Brunner M, Hollenstein U, Delacher S, Jager D, Schmid R, Lackner E, et al. Distribution and antimicrobial activity of ciprofloxacin in human soft tissues. Antimicrob Agents Chemother. 1999;43(5):1307–1309. doi: 10.1128/AAC.43.5.1307.
    1. Radiological protection in biomedical research . ICRP publication 62. Annals of ICRP. Oxford: Permagon Press; 1992.
    1. Rennard SI, Basset G, Lecossier D, O'Donnell KM, Pinkston P, Martin PG, et al. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol (1985) 1986;60(2):532–538. doi: 10.1152/jappl.1986.60.2.532.
    1. Taylor AE, Guyton AC, Bishop VS. Permeability of the alveolar membrane to solutes. Circ Res. 1965;16:353–362. doi: 10.1161/01.RES.16.4.353.
    1. van Duijn E, Sandman H, Grossouw D, Mocking JA, Coulier L, Vaes WH. Automated combustion accelerator mass spectrometry for the analysis of biomedical samples in the low attomole range. Anal Chem. 2014;86(15):7635–7641. doi: 10.1021/ac5015035.
    1. Olivera ME, Manzo RH, Junginger HE, Midha KK, Shah VP, Stavchansky S, et al. Biowaiver monographs for immediate release solid oral dosage forms: ciprofloxacin hydrochloride. J Pharm Sci. 2011;100(1):22–33. doi: 10.1002/jps.22259.
    1. Mulgaonkar A, Venitz J, Sweet DH. Fluoroquinolone disposition: identification of the contribution of renal secretory and reabsorptive drug transporters. Expert Opin Drug Metabol Toxicol. 2012;8(5):553–569. doi: 10.1517/17425255.2012.674512.
    1. Höffken G, Lode H, Prinzing C, Borner K, Koeppe P. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother. 1985;27(3):375–379. doi: 10.1128/AAC.27.3.375.
    1. Schuler P, Zemper K, Borner K, Koeppe P, Schaberg T, Lode H. Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, epithelial lining fluid, and polymorphonuclear leucocytes. Eur Respir J. 1997;10(5):1130–1136. doi: 10.1183/09031936.97.10051130.
    1. Gotfried MH, Danziger LH, Rodvold KA. Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest. 2001;119(4):1114–1122. doi: 10.1378/chest.119.4.1114.
    1. Conte JE, Jr, Golden J, Duncan S, McKenna E, Lin E, Zurlinden E. Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects. Antimicrob Agents Chemother. 1996;40(7):1617–1622. doi: 10.1128/AAC.40.7.1617.
    1. Baldwin DR, Wise R, Andrews JM, Gill M, Honeybourne D. Comparative bronchoalveolar concentrations of ciprofloxacin and lomefloxacin following oral administration. Respir Med. 1993;87(8):595–601. doi: 10.1016/S0954-6111(05)80262-8.
    1. Lettieri JT, Rogge MC, Kaiser L, Echols RM, Heller AH. Pharmacokinetic profiles of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 1992;36(5):993–996. doi: 10.1128/AAC.36.5.993.
    1. Lappin G, Boyce MJ, Matzow T, Lociuro S, Seymour M, Warrington SJ. A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung. Eur J Clin Pharmacol. 2013;69(9):1673–1682. doi: 10.1007/s00228-013-1528-2.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다