Determination of cidofovir in human plasma after low dose drug administration using high-performance liquid chromatography–tandem mass spectrometry

Momper, Jeremiah D.; Zhang, Shimin; Randhawa, Parmjeet; Shapiro, Ron; Schonder, Kristine S.; Venkataramanan, Raman

doi:10.1016/j.jpba.2010.06.034

Cited by 8 publications

(2 citation statements)

References 16 publications

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“…Cidofovir concentrations in EDTA-treated plasma were measured by using a validated liquid chromatography-tandem mass spectrometry method according to procedures described previously by Momper et al (16). Prestudy validation met all acceptance criteria set forth by applicable guidance by the U.S. Food and Drug Administration (17).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Brown

Cohen

Tong

et al. 2015

Antimicrob Agents Chemother

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fChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.A utologous and allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant hematological and immunological disorders results in a variable period of compromised immunity (1). T-lymphocyte numbers and function are decreased by chemotherapeutic conditioning regimens, certain stem cell processing techniques, and immunosuppressive agents used to prevent or treat graft-versus-host disease (GVHD) in allogeneic HSCT recipients (1). In addition, the graft source, such as cord blood, peripheral blood stem cells, or marrow, impacts the pace and quality of immune reconstitution. Consequently, children undergoing HSCT are at profound risk for serious and potentially fatal viral infections. Viruses that commonly complicate HSCT include adenoviruses, cytomegalovirus (CMV), herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), BK virus, and other community-acquired respiratory and gastrointestinal (GI) viruses (2-6). Furthermore, the need for protracted antiviral therapy due to impaired immune clearance increases the risk of antiviral resis...

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Brown

Cohen

Tong

et al. 2015

Antimicrob Agents Chemother

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“…The concentrations of cidofovir in plasma were determined by a previously reported validated liquid chromatographic-mass spectrometric method (22). Briefly, plasma samples were processed by an anion exchange solid phase extraction procedure and chromatography was performed using a Luna C8(2) analytical column, 5 lm, 150 9 3.0 mm, with isocratic elution.…”

Section: Analytical Methodologymentioning

confidence: 99%

Pharmacokinetics of low‐dose cidofovir in kidney transplant recipients with BK virus infection

Momper

Zhao

Shapiro

et al. 2012

Transplant Infectious Dis

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Background BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen is unknown in kidney transplant recipients. Methods We investigated the pharmacokinetics of low-dose cidofovir both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. Results The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m2 (range: 17 – 75 mL/min/1.73 m2). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir pharmacokinetics. Maximum cidofovir plasma concentrations, which averaged approximately 1 μg/mL, were significantly below the 36 μg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P> 0.05). Conclusions Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r2=0.8 without probenecid; r2=0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships in order to optimize the cidofovir dosing regimen for BKV infection.

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Liquid chromatography–mass spectrometry methods for the intracellular determination of drugs and their metabolites: a focus on antiviral drugs

Billat

Saint-Marcoux

2017

Anal Bioanal Chem

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Understanding the efficacy and/or toxicity of most drugs requires effective intracellular measurements of the drug and its metabolites. Nevertheless, the most common plasma marker of the biological effect of the drug is the area under the curve. Compared with drug determination in whole blood or urine, various difficulties occur in the development of analytical methods for intracellular measurements. We propose step-by-step guidelines to develop an analytical method exploring intracellular concentrations of antivirals and/or their metabolites. These guidelines are illustrated with the most sensitive liquid chromatography-mass spectrometry methods developed for human in vivo and in vitro studies. We summarize 18 studies that provided methods to explore intracellular concentrations of antivirals since 2002. To explore intracellular metabolites, two different approaches can be envisaged. The direct approach, most frequently using ion-pairing agents, is fast and requires only a small sample but is expensive. The indirect approach is the more widely used approach, but is cumbersome and time-consuming. In both cases, liquid chromatography-mass spectrometry has become the method of choice to determine intracellular drug concentrations with high sensitivity. These methods may increase our understanding of drug behavior in organisms. This is true for preclinical studies where the mechanism of action, the metabolism, and the toxicity of drugs are explored. It is also true for clinical applications when dose adjustment is needed and cannot rely on blood concentrations. Graphical Abstract Direct and indirect approaches to measure intracellular concentrations.

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Determination of cidofovir in human plasma after low dose drug administration using high-performance liquid chromatography–tandem mass spectrometry

Cited by 8 publications

References 16 publications

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Pharmacokinetics of low‐dose cidofovir in kidney transplant recipients with BK virus infection

Liquid chromatography–mass spectrometry methods for the intracellular determination of drugs and their metabolites: a focus on antiviral drugs

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