To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer.
A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III ...studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model.
A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t1/2) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P<0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance.
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.
Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be ...a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of (14)CSQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of (14)CSQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.
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 microM) in interacting with hSPNT1 was substantially higher than that of inosine (4.5 microM). 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 (approximately 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.
Recently, we cloned a human organic cation transporter, hOCT1, which is expressed primarily in the liver. hOCT1 plays an important role in the cellular uptake and elimination of various xenobiotics ...including therapeutically important drugs. HIV protease inhibitors are a new class of therapeutic agents. The purpose of this study was to elucidate the interactions of HIV protease inhibitors with hOCT1 and to determine whether hOCT1 is involved in the elimination of these compounds. We studied the interactions of HIV protease inhibitors with hOCT1 in a transiently transfected human cell line, HeLa. Uptake studies were carried out 40 h post-transfection using the radiolabeled model organic cation, (14)Ctetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC(50) of 62 microM), nelfinavir (IC(50) of 22 microM), ritonavir (IC(50) of 5.2 microM), and saquinavir (IC(50) of 8.3 microM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitors trans-stimulated (14)CTEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent "trans-inhibition" effect. No enhanced uptake of (14)Csaquinavir was observed in hOCT1 DNA-transfected cells versus empty vector-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibitors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Other transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.
Two open‐label, randomized, 2‐way crossover studies (1 single‐dose and 1 steady‐state) were conducted in healthy volunteers to compare the pharmacokinetics and pharmacodynamics of a novel ...extended‐release ciprofloxacin (ciprofloxacin ER; 500 mg once daily) and immediate‐release ciprofloxacin (ciprofloxacin IR; 250 mg twice daily). For both studies, mean ciprofloxacin maximum concentration (Cmax) values after once‐daily ciprofloxacin ER were significantly greater than those after the first daily dose of ciprofloxacin IR (P < .0001) but were lower than those after the second daily dose of ciprofloxacin IR (P < .05). The relative bioavailability of ciprofloxacin ER compared to ciprofloxacin IR was 93.8% in the single‐dose study and 97.7% in the steady‐state study. Mean urinary ciprofloxacin concentrations and excretion rates after either treatment were substantially greater than the minimum inhibitory concentrations (MICs) for susceptible uropathogens in both studies. The area under the concentration‐time curve (AUC)/MIC, Cmax/MIC, amount excreted (Ae)/MIC, and Ae24/MIC ratios with ciprofloxacin ER were similar to or slightly greater than with ciprofloxacin IR for all susceptible organisms.
Gradual soil acidification in the Columbia Basin (CB), Washington State, brings into question the validity of the traditional sodium bicarbonate (NaHCO3) extractable P (Olsen phosphorus, OP) method ...for making fertility recommendations. Our objectives were to determine how soil pH influences the soil P indices after fertilization and sorption capacity of soils with similar levels of available P at varying soil pH levels. Collected soils represented a range of pH (5.2–8.4) and OP (3–40 mg P kg−1). Soils were treated with 0, 44, 88, or 132 kg P ha−1 and incubated at 20°C for 6 wk. Subsamples were collected and analyzed for available P with OP, Bray P1 (BP1), modified Morgan (MMP), Mehlich-III (M3P) extractions. Additionally, P sorption isotherms were performed on untreated soils. Analysis of variance indicated that the slope of the change in extractable P was generally not significant (α = 0.05) for OP, BP1, MMP, and M3P given a P addition for several soils at different pH but of similar initial available P levels. Grouping soils by pH showed differences in slope with OP (0.27–0.34) yielding the least difference and MMP (0.12–0.33) the greatest related to soil pH. Langmuir parameters of b, sorption capacity, and k, binding energy, showed variability for soils grouped by initial available P for several pH levels. Grouped by pH there was little difference in P sorption in relation to soil pH. Continued use of OP on acidified soils of the CB appears to be a viable soil testing strategy.
Objective
The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of ...administration.
Study design
We used an open‐label, 6‐period, incomplete Latin square crossover study in 18 human immunodeficiency virus–negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24‐hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods.
Results
Median saquinavir area under the curve (AUC) increased by 62‐fold when ritonavir was coadministered, by 50‐fold when ritonavir was given 4 hours earlier, and by 16‐fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7‐fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5‐fold with coadministration of ritonavir and by 1.8‐ and 2.1‐fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes.
Conclusion
Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.
Clinical Pharmacology & Therapeutics (2003) 73, 406–416; doi: 10.1016/S0009‐9236(03)00006‐7
The overall goal of this study was to determine the mechanisms by which nucleobases are transported in the choroid plexus. Choroid plexus tissue slices were obtained from the lateral ventricles of ...rabbit brains and depleted of ATP with 2,4-dinitrophenol. In the presence of an initial inwardly directed Na+ gradient, hypoxanthine accumulated in the tissue slices against a concentration gradient. Na(+)-stimulated hypoxanthine uptake was saturable with a Km of 31.1 +/- 9.71 microM and a Vmax of 2.69 +/- 0.941 nmol/g/s (mean +/- S.E.). Na(+)-stimulated hypoxanthine uptake was inhibited by (100) microM naturally occurring purine and pyrimidine nucleobases (adenine, cytosine, guanine, hypoxanthine, thymine, uracil, and xanthine) as well as by the nucleoside analog, dideoxyadenosine. The stoichiometric coupling ratio between Na+ and hypoxanthine was 1.7:1. The data demonstrate the presence of a novel Na(+)-dependent nucleobase transporter in the choroid plexus, which is distinct from the previously described Na(+)-nucleoside transporter in choroid plexus and from Na(+)-dependent nucleobase transporters in other tissues in terms of its kinetics, substrate selectivity, and Na(+)-nucleobase stoichiometry. This transporter may play a role in the targeting of both salvageable nucleobases and therapeutic nucleoside analogs to the central nervous system.
The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many ...of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na(+)-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na(+)-driven 3H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC) on Na(+)-uridine transport was determined. At a concentration of 100 microM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na(+)-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na(+)-uridine uptake with a Ki of 26.4 microM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na(+)-nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The Ki of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.
The S-oxygenation of cimetidine was investigated using achiral chemical and chiral chemical and enzymatic S-oxygenation procedures. The products of the reactions were thoroughly characterized by ...spectral, chiroptical, chromatographic, and stereochemical correlation methods. S-Oxygenation by the Kagan method or in the presence of pig liver microsomes or pig liver flavin-containing monooxygenase (FMO) (form I) all gave essentially identical enantioselectivity: the average enantiomeric excess was -13.4% and the stereopreference was for formation of (+)-cimetidine S-oxide in a ratio of (+)56.7%:(-)43.3%. The profile of immunoreactivity and the effect of metabolism inhibitors on cimetidine S-oxide formation in the presence of pig liver microsomes were consistent with a role of FMO (form I) in enantioselective (+)-cimetidine S-oxide formation. Administration of cimetidine to seven healthy male volunteers provided pharmacokinetic parameters for cimetidine and cimetidine S-oxide that were typical of those for previously reported studies. The urinary cimetidine S-oxide was isolated and the stereopreference was for formation of (-)-cimetidine S-oxide in a ratio of (+)25.5%:(-)74.5%. In good agreement with the enantiomeric enrichment values observed for the adult human urinary metabolite, the relative configuration of cimetidine S-oxide formed in adult human liver microsomes was (+)-15.8%:(-)-84.2%. Because the enantioselectivity and profile of immunoreactivity and the effect of metabolism inhibitors on cimetidine S-oxygenation in adult human liver microsomes are consistent with a role of FMO (form II) in cimetidine S-oxide formation and because the enantioselectivity of cimetidine S-oxide observed in adult humans is similar, we conclude that in vivo, cimetidine is S-oxygenated principally by FMO (form II).
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