This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.
Many purine nucleosides and their analogs are actively transported in the kidney. Using homology cloning strategies and reverse transcriptase-polymerase chain reactions, we isolated a cDNA encoding a Na+-dependent nucleoside transporter, hSPNT1, from human kidney. Functional expression in Xenopus laevis oocytes identified hSPNT1 as a Na+-dependent nucleoside transporter that selectively transports purine nucleosides but also transports uridine. The Michaelis constant ( K m) of uridine (80 μM) in interacting with hSPNT1 was substantially higher than that of inosine (4.5 μM). hSPNT1 (658 amino acids) is 81% identical to the previously cloned rat Na+-nucleoside transporter, SPNT, but differs markedly from SPNT in terms of its primary structure in the NH2 terminus. In addition, an Alu repetitive element (∼282 bp) is present in the 3′-untranslated region of the hSPNT1 cDNA. Northern analysis revealed that multiple transcripts of hSPNT1 are widely distributed in human tissues including human kidney. In contrast, rat SPNT transcripts are absent in kidney and highly localized to liver and intestine. The hSPNT1 gene was localized to chromosome 15. This is the first demonstration of a purine nucleoside transporter in human kidney.
Aims Voxelotor (previously GBT440) is a haemoglobin (Hb) modulator that increases Hb‐oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once‐daily oral drug to treat sickle cell disease (SCD). This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. Methods A total of 40 healthy volunteers (100, 400, 1000, 2000 or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group). Twenty‐four healthy volunteers received multiple doses of voxelotor once daily for 15 days (300, 600 or 900 mg, n = 6 per group) or placebo (n = 2 per group). Results Voxelotor was well tolerated and exhibited a linear pharmacokinetic profile and a half‐life ranging from 61 ± 7 h to 85 ± 7 h. High partitioning into the RBC compartment provides evidence of highly specific binding to Hb. Voxelotor exhibited a concentration‐dependent left‐shift of oxygen equilibrium curves. Percent Hb modification following 900 mg voxelotor for 15 days was 38 ± 9%. Terminal half‐life of voxelotor in SCD patients (50 ± 3 h) was shorter than in healthy volunteers. Evaluation of erythropoietin, exercise testing, and haematologic parameters were consistent with normal oxygen delivery during both rest and exercise. Conclusion This first‐in‐human study demonstrates voxelotor was well tolerated in SCD patients and healthy volunteers and established proof of mechanism on increasing Hb‐oxygen affinity.
The nucleoside analog R1479 is a potent and highly selective inhibitor of nonstructural protein 5B-directed hepatitis C virus (HCV) replication in vitro. R1626, a tri-isobutyl ester prodrug of R1479, was developed to increase bioavailability and improve antiviral activity. A multicenter, observer-blinded, randomized, placebo-controlled, multiple ascending dose, phase 1b study was designed to evaluate the safety, pharmacokinetics, and antiviral activity and to potentially identify the maximum tolerated dose of R1626 in patients with chronic hepatitis C. Forty-seven treatment-naïve patients infected with HCV genotype 1 were treated with R1626 orally at doses of 500 mg, 1500 mg, 3000 mg, or 4500 mg or placebo twice daily for 14 days with 14 days of follow-up. Safety, tolerability, pharmacokinetics, and antiviral activity were assessed. Doses up to and including 3000 mg twice daily were well tolerated after 14 days of treatment. There was an increase in frequency of adverse events at the highest dose (4500 mg). Reversible mild to moderate hematological changes were observed with increasing doses. T he current standard of care for patients with chronic hepatitis C virus (HCV) infection, the combination of pegylated interferon alpha plus ribavirin for 48 weeks, results in sustained virological response in only approximately 50% of patients infected with HCV genotype 1. 1,2 Response rates are lower still in patients coinfected with human immunodeficiency virus, older patients, and those with cirrhosis. 3-5 Therefore, a considerable unmet medical need remains in this disease area, which will be addressed through the development of novel therapeutic approaches.One such approach is to target the HCV polymerase enzyme that is essential for HCV replication. The concept of polymerase inhibition to attain antiviral efficacy has been proven in viral infections such as hepatitis B virus, herpes simplex virus, and human immunodeficiency virus. Polymerase inhibitors form the largest class of approved antiviral drugs and, of these, nucleoside analogs constitute the largest chemical class. Nucleoside analogs are metabolized by cellular enzymes to the corresponding nucleoside triphosphate analogs, which competitively inhibit viral nucleic acid synthesis.Abbreviations: AE, adverse event; ALT, alanine aminotransferase; HCV, hepatitis C virus; NS5B, nonstructural protein 5B; SAE, serious adverse event. From the
The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.
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