Bertucci, R.

Bonasso, M.

Bonora, Stefano

Bramato, C.

Calcagno, Andrea

D&apos

Di Perri, Giovanni

Ghisetti, V.

Imperiale, D.

Marinaro, L.

Orofino, G.

Salassa, B.

Simiele, Marco

Tettoni, Mc

Trentini, L.

English

D'Avolio, Antonio

DI PERRI, Giovanni

Institutional Research Information System University of Turin

14 December 2021AperTO - Archivio Istituzionale Open Access dell'Università di TorinoMONITORING OF VIROLOGICAL AND PHARMACOLOGICAL CEREBROSPINAL FLUID PARAMETERS IN HAART-TREATED HIV-POSITIVE PATIENTS IN THE CLINICAL SETTING / Calcagno A ; Bonora S ; Tettoni MC ; Bonasso M ;Salassa B ; Orofino G ; Bramato C ; Trentini L ; Simiele M ; Marinaro L ; Bertucci R ; Imperiale D ; D'Avolio A ; Ghisetti V; Di Perri G. - In: INFECTION. - ISSN 0300-8126. - 39(2011), pp. S35-S36. ((Intervento presentato al convegno 6th IASon HIV Pathogenesis, Treatment and Prevention. 2011 tenutosi a Rome, Italy nel 17/07/2011.Original Citation:MONITORING OF VIROLOGICAL AND PHARMACOLOGICAL CEREBROSPINAL FLUID PARAMETERS IN HAART-TREATED HIV-POSITIVE PATIENTS IN THE CLINICAL SETTINGTerms of use:Open Access(Article begins on next page)Anyone can freely access the full text of works made available as "Open Access". Works made available under aCreative Commons license can be used according to the terms and conditions of said license. Use of all other worksrequires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law.Availability:This is the author's manuscriptThis version is available http://hdl.handle.net/2318/97352 sinceMediterr J Hematol Infect Dis 2012; 4; Open Journal System MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASESCase ReportsTuberculosis After Gastrectomy, Plasmatic De Socio Giuseppe Vittorio 1, D’Avolio AntonioGiovanni 2 and Baldelli Franco11 Department of Infectious Diseases “Santa Maria della Misericordia” Hos2 Laboratory of Clinical Pharmacology and Pharmacogenetic, Department of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Turin, ItalyCorrespondence to: Giuseppe Vittorio L De Socio, MD PhDPerugia, Ospedale "Santa Maria della Misericordia", piazzale Menghini, 1 5784321, Fax: +39-075-5784346. E-mail: Competing interests: The authors have declared thPublished: January 24, 2012Received: October 14, 2011Accepted: December 27, 2011Mediterr J Hematol Infect Dis 2012, 4(1): e201This article is available from: http://www.mjhid.org/article/view/9336This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/2.0provided the original work is properly citedAbstract. We report pharmacokinetic data on two gastrectomized, patients affected bytuberculosis. Drugs plasmatic concentrations were measured after seven days of oral therapy by a validated high performance liquid chromatographythe area under the concentration-therapeutic level of isoniazid was found in a patient with total gastrectomy mg\L and AUC0-24 level of 4.75 hr*mg/L. The level of the oThese findings support the need to monitor anti tubercular drug levels to facilitate early detection of therapeutic failure, above all in patients treated with isoniazid and with potential problems on oral drugs absorption.Introduction. Little is known of antitubercular treatment in gastrectomized patients. Bysearch we found no evidence in the literature regarding the antitubercular drugs absorption after gastrectomy. Total and partial gastric resection alters the anatomy and secretory activity of the gastrointestinal tract. It might be expected that the consequences of such changes should affect the pharmacokinetics, econcerning the absorption of orally administered drugs that are primarily absorbed in the stomach or duodenum leading to sub-therapeutic drugs level. Case Studies and Methods. We report here the case of two consecutive gastrectomized patients awww.mjhid.org ISSN 2035-3006Concentration of Antitubercular Drugs2, Sgrelli Alessio1, Baietto Lorena 2, Lisa Malincarnepital, University of Perugia, Perugia Italy. Clinica di Malattie Infettive, Università degli Studi di – 06129 Perugia, Italygiuseppedesocio@yahoo.itat no competing interests exist.207, DOI 10.4084/MJHID.2012.007), which permits unrestricted use, distribution, and reproduction in any medium, .-mass spectrometry (HPLCtime-curve (AUC) over 24 hours (AUC0-24ther antitubercular drugs was adequate. a MEDLINE specially ffected by tuberculosis. To estimate the degree to which absorption is impaired, the drug levels were measured in duplicate plasma samples. The patients were fasting at the time of drugs intake. Plasma sample levels were measured by a validated high perforchromatography-mass spectrometry (HPLCmethod with the following lower limit of quantification (LOQ) and detection (LOD): 0.015 mg/L (LOQ) and 0.007 mg/L (LOD) for isoniazid; 0.195 mg/L (LOQ) and 0.048 mg/L (LOD) for pyrazinamide; 0.019 mg(LOQ) and 0.008 mg/L (LOD) for rifampin; 0.020 mg/L (LOQ) and 0.010 mg/L (LOD) for ethambutol.Non-compartmental pharmacokinetic analysis of the data was performed using Kinetica version 5.0 1, Di Perri . Tel: +39-075--MS) method and ) was calculated. A sub-with a Cmax of 0,395 mance liquid -MS) /L Mediterr J Hematol Infect Dis 2012; 4: Open Journal Systemsoftware (Thermo Fisher Scientific). The area under the concentration-time curve (AUC) over 24 hours (AUC0-24) in plasma was calculated by the linear-log trapezoidal rule, using the same Ctrough concentration for time 0 and 24 and applying a limited sampling model.1Case 1. A 68-year-old, HIV negative was affected by tubercular (TB) epididymitis. His previous medical history was remarkable for a total gastrectomy with Roux-en-Y gastric bypass procedure performed five years before, due to gastric cancer. His renal and liver function was normal. His weight was 65Kg. He was treated with standard oral anti TB therapy including isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 1200 mg daily and pyrazinamide 2000 mg daily, vitamin B6 300 mg daily. His chronic medications were: enalapril 20 mg daily, amlodipine 5 mg daily, ticlopidine 500 mg daily. Therefore plasma concentrations of anti TB drugs were measured after seven days of drug intake in the hospital. Plasma samples were collected before the drug intake to measure Ctrough and after 2 hours to measure Cmax (peak plasma concentration). We found very low Cmax and AUC0-24 levels of isoniazid (0,395 mg\L and 4.75 hr*mg/L respectively), not attributable to patient’s anti-hypertensive and anti-tubercular drug-drug interaction. The results of plasma concentrations,AUC0-24 and the therapeutic expected range are shown in the following table. The patient obtained slow clinical improvement. Case 2. A 65-year-old HIV negative woman was affected by pulmonary tuberculosis. She underwent a partial gastrectomy for a gastric ulcer 15 years earlier. Her weight was 39 Kg; she was treated with standard anti TB therapy including isoniazid 250 mg daily, rifampin 600 mg daily, ethambutol 1000 mg daily and pyrazinamide 1000 mg daily, vitamin B6 300 mg daily. The drugs were administered intra venous (iv) in the first 15 days and oral subsequently (pyrazinamide and vitamin B6 were always administered orally). No other drugs were taken by this patient. We studied the plasmatic drugs concentration in the course of iv and oral therapy. Plasma samples were collected before the daily drug intake to measure Ctrough and after 2 hours and 5 hours to measure Cmax. The results of plasma concentrations, AUC0-24 during oral therapy are shown in the table. During iv therapy the measured AUC0-24was very similar from the one reported in the course of oral treatment: isoniazid 26.70 hr*mg/L, rifampin 154.87 hr*mg/L, ethambutol 32.48 hr*mg/L. The patient obtained adequate clinical response.Discussion. To our knowledge, data regarding the first line antitubercular drugs absorption after gastrectomy are scantily. Overall the measured plasmatic antitubercular drugs in gastrectomized patients were generally adequate. We observed that a patient undergoing a complete gastric resection followed by a Roux-en-Y gastric bypass procedure (case 1) had poor isoniazid plasmatic level. In the second case with the patient who had undergone a partial gastric resection, the absorption of isoniazid was right and comparable to iv administration. Rifampin, ethambutol and pyrazinamide in both patients always had suitable level.Obviously, a single case study has several limitations principally linked to individual variability, thus we can’t draw conclusions. In addition, in case 1we have calculated the AUC0-24 from two determinations only according to a validated limitedTable 1. Anti-tubercular drugs plasma concentration and therapeutic range references.Anti tubercular drugs Time after dose, hPatient 1Patient 1Patient 1 AUC0-24(hr*mg/L)Patient 2Patient 2Patient 2 AUC0-24(hr*mg/L)Expected therapeutic references mg/LExpected range of AUC0-24(hr*mg/L)(Cmax, Ctrough)dose mg/dayDrug plasma concentration mg/Ldose mg/dayDrug plasma concentration mg/L(Cmax and Cut-off Cmax)Isoniazid  2300 (4.6)*0.3954.75250 (6.4)*5.0537.61Cmax 9-15[5] Cut-off Cmax 3.0 [5]10.52 -111.80 [8,9]5 ND 2.224 < 0.007 (LOD) 0.03Rifampin 2600 (9.2)*9.671116.40 600 (15)*12.67145.37Cmax 9.65- 24.99 [6] Cut-off Cmax 8.0 [7]47.40.-142.73 [6]5 ND 9.6424 0.029 0.72ethambutol  21200 (18.5)*4.54754.581000 (25)*7.0857.43 Cut-off Cmax 2.0 [6] ND5 ND 2.9424 < 0.010 (LOD) 0.70pyrazinamide 22000 (30.7)*47.2695832.501000 (25)*32.53337.22Cmax 21.70- 42.64 [6] Cut-off Cmax 35.0 [7]303.35-541.36 [6]5 ND 21.5424 13.346 1.84Area under the concentration-time curve (AUC0-24); lower limit of detection (LOD); *mg per Kg per day; ND=unavailable.Mediterr J Hematol Infect Dis 2012; 4: Open Journal Systemsampling model,1 and assuming Cmax appropriate after two hours of drugs intake. Even considering these limitations, we believe the observation is important at least for two reasons: firstly, it is known that gastrectomy patients have greater risk of having tuberculosis in later life and preventive therapy is mainly based on isoniazid administration;2,3 secondly, low serum concentration of antitubercular drugs have been associated with treatment failure, relapse and drug resistance.4Although the clinical significance of low concentration should be defined, it may be necessary to optimise drug dosages by TDM, especially in patients with an inadequate clinical response. These findings support the need to monitor anti tubercular drug levels to facilitate early detection of therapeutic failure above all in patients with potential problems on oral drugs absorption.References: 1. Kayano Y, Horiuchi I, Mori YI, Ishida K, Saito T, Taguchi M, Hashimoto Y. A simulation study to evaluate limited sampling strategies to estimate area under the curve of drug oncentration versus time following repetitive oral dosing: limited sampling model versus naive trapezoidal method. Biol Pharm Bull. 2009;32:1486-90. http://dx.doi.org/10.1248/bpb.32.14862. Steiger Z, Nickel WO, Shannon GJ, Nedwicki EG, Higgins RF.Pulmonary tuberculosis after gastric resection. Am J Surg. 1976;131:668-71. http://dx.doi.org/10.1016/0002-9610(76)90174-43. Snider DE Jr. Tuberculosis and gastrectomy. Chest. 1985;87:414-5http://dx.doi.org/10.1378/chest.87.4.414 PMid:39791264. Um SW, Lee SW, Kwon SY, Yoon HI, Park KU, Song J, et al. Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels. Int J Tuberc Lung Dis. 2007;11:972-8. PMid:177059745. Kimerling ME, Phillips P, Patterson P, Hall M, Robinson CA, Dunlap NE. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. Chest. 1998;113:1178-83http://dx.doi.org/10.1378/chest.113.5.1178 PMid:95962916. Peloquin CA, Jaresko GS, Yong CL, Keung AC, Bulpitt AE, Jelliffe RW. Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrob Agents Chemother. 1997;41:2670-9. PMid:9420037 PMCid:1641877. Chideya S, Winston CA, Peloquin CA, Bradford WZ, Hopewell PC, Wells CD et al. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis. 2009;48:1685-94.http://dx.doi.org/10.1086/599040 PMid:194325548. Donald PR, Parkin DP, Seifart HI, Schaaf HS, van Helden PD, Werely CJ et al. The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol. 2007;63:633-9. http://dx.doi.org/10.1007/s00228-007-0305-5PMid:175058219. Weiner M, Burman W, Vernon A, Benator D, Peloquin CA, Khan A et al. Tuberculosis Trials Consortium. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. Am J Respir Crit Care Med. 2003;167:1341-7. http://dx.doi.org/10.1164/rccm.200208-951OCPMid:12531776

MONITORING OF VIROLOGICAL AND PHARMACOLOGICAL CEREBROSPINAL FLUID PARAMETERS IN HAART-TREATED HIV-POSITIVE PATIENTS IN THE CLINICAL SETTING

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MONITORING OF VIROLOGICAL AND PHARMACOLOGICAL CEREBROSPINAL FLUID PARAMETERS IN HAART-TREATED HIV-POSITIVE PATIENTS IN THE CLINICAL SETTING

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