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BACKGROUND: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).
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Apolipoproteína L1 , Glomerulosclerose Segmentar e Focal , Proteinúria , Animais , Humanos , Camundongos , Apolipoproteína L1/antagonistas & inibidores , Apolipoproteína L1/genética , Apolipoproteínas/genética , Negro ou Afro-Americano , Creatinina/urina , Mutação com Ganho de Função , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/genética , Células HEK293 , Proteinúria/tratamento farmacológico , Proteinúria/genéticaRESUMO
OBJECTIVE: Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. MATERIALS AND METHODS: This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. RESULTS: 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) µg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×µg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×µg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. CONCLUSION: A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.
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Anticorpos Monoclonais Humanizados/farmacologia , Anticolesterolemiantes , Voluntários Saudáveis , Hong Kong , Humanos , Masculino , Pró-Proteína Convertase 9 , Resultado do TratamentoRESUMO
AIMS: Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner. METHODS: An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded. RESULTS: Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) dayâ¢ng ml(-1) (serum) and 5220 (4880) dayâ¢ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab. CONCLUSIONS: These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.
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Conservadores da Densidade Óssea/farmacocinética , Denosumab/farmacocinética , Troca Materno-Fetal , Sêmen/metabolismo , Vagina/metabolismo , Adulto , Idoso , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/sangue , Denosumab/administração & dosagem , Denosumab/sangue , Feminino , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gravidez , RiscoRESUMO
CONTEXT: For adults with end-stage kidney disease, live donor kidney transplant (LDKT) has better outcomes than long-term dialysis and deceased donor kidney transplant. However, black patients receive LDKT at a much lower rate than adults of any other race or ethnicity. OBJECTIVE: To examine the LDKT readiness stage of black patients on the transplant waiting list and its association with LDKT knowledge, concerns, and willingness. DESIGN: Cross-sectional analysis of baseline data from a randomized controlled trial to improve knowledge and reduce concerns about LDKT.Patients and Setting-One hundred fifty-two black patients on the kidney transplant waiting list at a single transplant center in the northeastern United States. MAIN OUTCOME MEASURES: LDKT readiness stage, knowledge, concerns, and willingness to talk to others about living donation. RESULTS: Sixty percent of patients were not considering or not yet ready to pursue LDKT, and only 11% had taken action to talk to family members or friends about the possibility of living kidney donation. Patients in later stages of LDKT readiness (ie, who had talked to others about donation or were preparing to do so) had significantly more knowledge (P<.001), fewer concerns (P=.002), and more willingness (P=.001) to talk to others about living donation than those in earlier readiness stages. CONCLUSIONS: The large percentage of black patients who are in the earlier stages of LDKT readiness may account for the low rate of LDKT in this patient population at our transplant center. Innovative and tailored LDKT educational strategies for black patients are needed to help reduce racial disparities in LDKT.
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Negro ou Afro-Americano , Transplante de Rim , Doadores Vivos , Listas de Espera , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e Questionários , Estados UnidosRESUMO
Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.
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Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.
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Cálcio/metabolismo , Magnésio/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Animais , Cálcio da Dieta/metabolismo , Fator de Crescimento de Fibroblastos 23 , Homeostase/genética , Homeostase/fisiologia , Camundongos , Camundongos Knockout , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/fisiologia , Receptores de Detecção de Cálcio , Receptores Acoplados a Proteínas G/genética , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMO
BACKGROUND: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures. METHODS: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH). RESULTS: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
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Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Fraturas do Quadril/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. METHODS: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients. RESULTS: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
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Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Fixação de Fratura , Fraturas da Tíbia/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Consolidação da Fratura , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
1Alpha,25(OH)(2) vitamin D(3) [1,25(OH)(2)D(3)] increases serum Ca(2+) concentration in vivo, an action counteracted by activation of the Ca(2+)-sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca(2+) excretion. Relatively little is known of the role the CaSR plays in this response through its potentially direct actions in kidney, gut, and bone independently of PTH. We report PTH-independent roles of the CaSR in modulating the response to exogenous 1,25(OH)(2)D(3) in mice with targeted disruption of both the CaSR and PTH genes (C(-)P(-)) compared with that in mice with disruption of the PTH gene alone (C(+)P(-)) or wild-type mice (C(+)P(+)). After intraperitoneal injection of 0.5 ng/g body wt 1,25(OH)(2)D(3), peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca(2+) in C(-)P(-) mice than in the other genotypes on a Ca(2+)-replete diet that was attenuated by a Ca(2+)-deficient diet and pamidronate, 2) increased urinary Ca(2+)-to-creatinine ratios (UCa/Cr) in the C(+)P(-) and C(+)P(+) mice but a lowered ratio in the C(-)P(-) mice on a Ca(2+)-replete diet, and 3) no increase in calcitonin (CT) secretion in the C(+)P(+) and C(+)P(-) mice and a small increase in the C(-)P(-) mice. PTH deficiency had the anticipated effects on the expression of key genes involved in Ca(2+) transport at baseline in the duodenum and kidney, and injection of 1,25(OH)(2)D(3) increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca(2+) seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)(2)D(3) in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)(2)D(3)-mediated gut Ca(2+) absorption and decreased renal Ca(2+) excretion, without any differences in bone-related release of Ca(2+) or CT secretion among the three genotypes that could explain the differences in their calcemic responses.
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Cálcio/metabolismo , Duodeno/metabolismo , Ergocalciferóis/farmacocinética , Rim/metabolismo , Hormônio Paratireóideo/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Calcitonina/metabolismo , Cálcio/sangue , Cálcio/urina , Cálcio da Dieta/administração & dosagem , Cálcio da Dieta/metabolismo , Creatinina/urina , Difosfonatos/farmacologia , Duodeno/efeitos dos fármacos , Ergocalciferóis/administração & dosagem , Ergocalciferóis/sangue , Regulação da Expressão Gênica , Genótipo , Injeções Intraperitoneais , Absorção Intestinal , Rim/efeitos dos fármacos , Camundongos , Camundongos Knockout , Pamidronato , Hormônio Paratireóideo/deficiência , Hormônio Paratireóideo/genética , Fenótipo , Receptores de Detecção de Cálcio/deficiência , Receptores de Detecção de Cálcio/genéticaRESUMO
The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca(2+)(o)). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR(+/+) PTH(-/-), referred to as C(+)P(-)), lacking both CaSR and PTH (CaSR(-/-) PTH(-/-), C(-)P(-)) or wild-type (CaSR(+/+) PTH(+/+), C(+)P(+)) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca(2+) load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C(-)P(-) mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C(+)P(-) mice defend against hypercalcemia similarly to C(+)P(+) mice. Reduced renal Ca(2+) clearance contributes to the intolerance of the C(-)P(-) mice to Ca(2+) loads, as they excrete less Ca(2+) at any given Ca(2+)(o) than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca(2+) handling. In addition, C(+)P(+) and C(+)P(-), but not C(-)P(-), mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)(2)D(3) in C(-)P(-) mice, in contrast, was similar to those in C(+)P(-) and C(+)P(+) mice during an oral Ca(2+) load, indicating that increased 1,25(OH)(2)D(3) production cannot account for the oral Ca(2+)-induced hypercalcemia in the C(-)P(-) mice. Thus, CaSR-stimulated PTH release serves as a "floor" to defend against hypocalcemia. In contrast, high-Ca(2+)(o)-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca(2+)(o)-stimulated, CaSR-mediated CT secretion and renal Ca(2+) excretion, and perhaps other factors, serve as a "ceiling" to limit hypercalcemia resulting from various types of hypercalcemic challenges.
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Hipercalcemia/fisiopatologia , Hormônio Paratireóideo/fisiologia , Receptores de Detecção de Cálcio/fisiologia , Aminoácidos/urina , Animais , Osso e Ossos/metabolismo , Calcifediol/metabolismo , Calcitonina/sangue , Cálcio/sangue , Cálcio/farmacologia , Cálcio/urina , Implantes de Medicamento , Homeostase/genética , Homeostase/fisiologia , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocalcina/sangue , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/farmacologia , Fosfatos/deficiência , Receptores de Detecção de Cálcio/genéticaRESUMO
The long-term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002-November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (<90 d from LT) (EC) vs. late conversion (LC). Renal function was evaluated using the six-point modification of diet in renal disease formula (estimated glomerular filtration rate [eGFR]). Forty-two patients on SRL and 40 on CNI had at least three months of follow-up and are included in the eGFR evaluation. At all time points after conversion, the EC group demonstrated a significantly higher mean eGFR than those in the LC group. A significant improvement in eGFR was seen within the EC group when comparing eGFR at time of conversion to eGFR at three, six, nine, and 12 months after conversion and last follow-up. The only improvement in the LC group was from conversion to the three-month time point. We conclude that EC to SRL results in a profound improvement in eGFR that begins at three months and is sustained beyond one yr.
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Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Rim/fisiologia , Transplante de Fígado/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Sirolimo/uso terapêutico , Inibidores de Calcineurina , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; Cmax , P = .23; AUClast , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by Cmax and AUClast , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , LDL-Colesterol/sangue , Falência Renal Crônica/tratamento farmacológico , Rim/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Área Sob a Curva , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Injeções Subcutâneas , Rim/fisiopatologia , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Inibidores de PCSK9 , Pró-Proteína Convertase 9/sangue , Ligação Proteica , Diálise RenalRESUMO
PURPOSE: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects. SUBJECTS AND METHODS: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast). RESULTS: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 µg/mL and 67.6 (15.2) µg/mL, respectively, and mean (SD) AUClast was 166 (55) day·µg/mL and 1110 (274) day·µg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo). CONCLUSION: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.
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The extracellular calcium (Ca2+o)-sensing receptor (CaSR) enables the parathyroid glands and other CaSR-expressing cells involved in calcium homeostasis, such as the kidney and bone, to sense alterations in the level of Ca2+o and to respond with changes in function that are directed at normalizing the blood calcium concentration. Several disorders of Ca2+o sensing arise from inherited or acquired abnormalities that 'reset' the serum calcium concentration upwards or downwards. Heterozygous inactivating mutations of the CaSR produce a benign form of hypercalcaemia, termed 'familial hypocalciuric hypercalcaemia', while homozygous mutations produce a much more severe hypercalcaemic disorder resulting from marked hyperparathyroidism, called 'neonatal severe hyperparathyroidism'. Activating mutations cause a hypocalcaemic syndrome of varying severity, termed 'autosomal-dominant hypocalcaemia or hypoparathyroidism' as well as Bartter's syndrome type V. Calcimimetic CaSR activators and calcilytic CaSR antagonists have also been developed with potential for use in the treatment of these disorders.
Assuntos
Hipercalcemia/genética , Hipocalcemia/genética , Receptores de Detecção de Cálcio/genética , Síndrome de Bartter/genética , Humanos , Hiperparatireoidismo Primário/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/fisiopatologia , Rim/fisiologia , Mutação de Sentido Incorreto , Glândulas Paratireoides/metabolismo , Polimorfismo Genético , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/metabolismo , Receptores de Detecção de Cálcio/fisiologia , Distribuição TecidualRESUMO
Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease. Hepatic cysts often are multiple, and in renal transplant recipients, occult infection with or without concurrent kidney cyst infection is a frequent cause of abdominal pain and fever and may require long-term antibiotic use and hospitalization. Rupture and bleeding of hepatic cysts into the peritoneum or viscera are infrequent complications that have been reported. Identification of a single culprit lesion that could be targeted for surgical intervention often is difficult because such imaging studies as computed tomographic scans, magnetic resonance images, or radionuclide-tagged white cell scans often show several inflamed cysts that can persist over several subsequent scans. Treatment may require surgical intervention. Eradication of infection and wound healing also is made difficult by concomitant immunosuppression in renal transplant recipients. We present the case of a renal transplant recipient with an infected dominant polycystic liver cyst that ruptured into the pericardium, leading to tamponade.
Assuntos
Cistos/complicações , Hepatopatias/complicações , Rim Policístico Autossômico Dominante/complicações , Idoso , Tamponamento Cardíaco/etiologia , Comorbidade , Doença da Artéria Coronariana/epidemiologia , Cistos/microbiologia , Evolução Fatal , Humanos , Transplante de Rim , Hepatopatias/microbiologia , Masculino , Pericárdio/patologia , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/cirurgia , Ruptura , Tomografia Computadorizada por Raios XRESUMO
Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [14C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [14C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.
Assuntos
Radioisótopos de Carbono/farmacocinética , Soluções para Diálise/metabolismo , Peptídeos/farmacocinética , Diálise Renal , Eliminação Renal/fisiologia , Insuficiência Renal Crônica/metabolismo , Administração Intravenosa , Adulto , Idoso , Biotransformação/efeitos dos fármacos , Biotransformação/fisiologia , Radioisótopos de Carbono/sangue , Radioisótopos de Carbono/urina , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/sangue , Peptídeos/urina , Traçadores Radioativos , Diálise Renal/tendências , Eliminação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/terapiaRESUMO
Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open-label, parallel-group study evaluated the pharmacokinetics of evolocumab in hepatic-impaired (Child-Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL-C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere-Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration -34%; mean area under the concentration-time curve (AUC) -47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were -57% (-64% to -48%), -70% (-75% to -63%), and -53% (-61% to -43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/sangue , Imunoglobulina G/administração & dosagem , Imunoglobulina G/sangue , Hepatopatias/sangue , Pró-Proteína Convertase 9/sangue , Adulto , Anticorpos Monoclonais Humanizados , LDL-Colesterol/sangue , Feminino , Humanos , Injeções Subcutâneas , Hepatopatias/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The pegfilgrastim on-body injector (OBI) is a single-use, disposable, battery-powered injector that is designed to automatically deliver a single subcutaneous dose of pegfilgrastim beginning approximately 27 hours after activation and continuing over approximately 45 minutes. In this open-label study, we assessed performance of the OBI delivering placebo buffer in healthy volunteers. RESEARCH DESIGN AND METHODS: Healthy men and women aged 18-55 years, with a body mass index of 18-35 kg/m2, were enrolled. OBIs were activated by filling them with placebo buffer, and two injectors were applied concurrently to each subject: one to the abdomen and one to the back of the upper arm. Subjects were monitored for substantial leakage during and after administration. MAIN OUTCOME MEASURES: The primary endpoint of the study was successful delivery of placebo buffer based on a composite of the following: no substantial leakage during or after administration, green status light indicator on the injector during and after administration, and fill indicator bar at the empty position after administration. The secondary endpoint was the incidence of treatment-emergent adverse events (AEs). RESULTS: Of the 150 subjects enrolled, 149 (99.3%) completed the study. Study subjects were 48.0% men, and 52.0% women; 47.3% were white, 35.3% black or African American, 12.7% Asian, and 4.7% other. Mean (SD) age was 35.9 (10.8) years. Of the 297 total deliveries, 292 (98.3%) were considered successful: 147/149 (98.7%; 95% confidence interval [CI]: 95.2%-99.6%) to the abdomen and 145/148 (98.0%; 95% CI: 94.2%-99.3%) to the back of the upper arm. Five deliveries were considered unsuccessful: two due to hazard alarms, and three due to substantial leakage. The most common treatment-emergent AEs (in >2% of subjects overall) by preferred term were medical device site reaction (20.7%), catheter-site hemorrhage (8.7%), and headache (3.3%). No serious AEs were reported. CONCLUSIONS: The pegfilgrastim OBI was well tolerated, and deliveries of placebo buffer were successful 98.3% of the time. The generalizability of these results may be limited by the conduct of this study in healthy subjects in a controlled environment.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neutropenia/prevenção & controle , Adolescente , Adulto , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Voluntários Saudáveis , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Placebos , Polietilenoglicóis , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.