Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal Function

Mita, Alain C.; Sweeney, Christopher J.; Baker, Sharyn D.; Goetz, Andrew; Hammond, Lisa A.; Patnaik, Amita; Tolcher, Anthony W.; Villalona‐Calero, Miguel A.; Sandler, Alan; Chaudhuri, Tuhin K.; Molpus, Kathleen; Latz, Jane E.; Simms, Lorinda; Chaudhary, Archana; Johnson, Robert D.; Rowinsky, Eric K.; Takimoto, Chris H.

doi:10.1200/jco.2004.00.9720

Cited by 104 publications

(99 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The effects of CKD on fu have been reported for some drugs with medium to high protein binding capacities such as cefazolin, pemetrexed, and sitagliptin. 20,25,66 There were no differences between the fu values measured in healthy volunteers and patients with CKD for pemetrexed (fu = 0.23) and sitagliptin (fu = 0.64). 20,66 The values of fu of cefazolin increased from 0.16 to 0.28 in patients with CKD Stage 4.…”

Section: Clinical Evidence Supporting the Role Of Uremic Solutes In Mmentioning

confidence: 86%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

View full text Add to dashboard Cite

One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

show abstract

Section: Clinical Evidence Supporting the Role Of Uremic Solutes In Mmentioning

confidence: 86%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

View full text Add to dashboard Cite

show abstract

“…There was no hepatic toxicity, but there was mild reversible renal toxicity with pemetrexed doses of 600 to 700 mg/m 2 (111). Although pemetrexed plasma clearance decreases with decreasing GFR, a pemetrexed dose of 500 mg/m 2 is tolerated in patients with GFR levels of 40 to 79 mL/min (112). Because a reduction in pemetrexed plasma clearance was associated with aspirin (110), and because nonsteroidal anti-inflammatory drugs are known to suppress antifolate renal tubular secretion (113), cessation of nonsteroidals has been required 2 to 5 days before pemetrexed administration.…”

Section: Contrasting 5-fluorouracil and Pemetrexedmentioning

confidence: 99%

Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

Chattopadhyay

Moran

Goldman

2007

Molecular Cancer Therapeutics

245

228

View full text Add to dashboard Cite

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non -small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. This review traces the history of antifolates that led to the development of pemetrexed and describes the unique properties of this agent that distinguish it from other antifolates. These include (a) its very rapid conversion to active polyglutamate derivatives in cells that build to high levels and are retained for long intervals to achieve prolonged and potent inhibition of its major target enzyme thymidylate synthase, (b) its high affinity for three folate transporters, and (c) its marked sensitivity to the level of physiologic folates in cells. The latter results in the unique and paradoxical finding that when transport mediated by the major folate transporter (the reduced folate carrier) is impaired, pemetrexed activity is preserved. This is due to concurrent contraction of competing cellular physiologic folates and utilization of a novel second transport carrier for which pemetrexed has high affinity, recently identified as the proton-coupled folate transporter (PCFT). Laboratory studies are reviewed that raise the possibility of new approaches to the use of folic acid supplementation in clinical regimens with pemetrexed. [Mol Cancer Ther 2007;6(2):404 -17]

show abstract

“…Three months before his present admission to the hospital, the patient was started on treatment with pemetrexed (500 mg/m 2 i.v., total dose 1 g, day 1), folic acid (350 mcg/day p.o. ), vitamin B 12 (1 g/60 days i.m. ), and dexamethasone (4 mg bid for 3 days).…”

Section: Case Reportmentioning

confidence: 99%

“…Pemetrexed is eliminated as unchanged drug primarily from the kidney, by both tubular secretion and glomerular filtration with the former being the predominant mechanism for patients with normal renal function. 12 Folates and antifolates are reabsorbed at kidney proximal tubules via folate receptors and transported into cells. [13][14][15] We hypothesize that the accumulation of the drug intracellularly and the subsequent inhibition of purine and protein synthesis, result in tubular cytotoxicity and possibly secondary tubulointerstitial inflammation leading to AKI.…”

mentioning

confidence: 99%

Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed

et al. 2010

View full text Add to dashboard Cite

We present a case of interstitial nephritis and nephrogenic diabetes insipidus (NDI) in a patient treated with pemetrexed (500 mg/m 2 ) for non-small cell lung cancer. Renal impairment and diabetes insipidus appeared after the first treatment cycle while he totally received four cycles of chemotherapy. There was not any significant myelosuppression and the patient was on regular supplementation with folic acid and vitamin B 12 . He was not on any other medications and he did not receive any nephrotoxic agents. Kidney biopsy showed acute tubular necrosis together with interstitial inflammatory infiltrate of mononuclear cells and interstitial fibrosis occupying 25% of the cortex. There was not any improvement of renal function after a 2-week trial of oral prednisone. In the present case report, we review the literature for pemetrexed-induced renal toxicity and the possible mechanisms involved.

show abstract

Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal Function

Abstract: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

Cited by 104 publications

References 35 publications

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed

Contact Info

Product

Resources

About