Pharmacokinetics, pharmacodynamics, and exposure-efficacy of dupilumab in adults with atopic dermatitis.

The pharmacokinetics (PKs) and exposure-efficacy of dupilumab have not been fully described for adults with atopic dermatitis (AD). Our objectives were to analyze the PKs and exposure-efficacy of dupilumab in adults with AD and compare the results of Japanese and overall populations. Adults with moderate-to-severe AD were randomly assigned to dupilumab (300 mg weekly [qw] or every 2 weeks [q2w], 200 mg q2w, 300 mg every 4 weeks [q4w], or 100 mg q4w) or placebo for 16 weeks in a randomized, double-blind, placebo-controlled, dose-ranging phase IIb trial (NCT01859988). This analysis included 379 patients (58 Japanese). Functional dupilumab concentrations increased in a dose-dependent manner; at lower concentrations, increases were greater than dose-proportional because of nonlinear, target-mediated clearance. Dupilumab pharmacokinetics were comparable in Japanese and non-Japanese patients with similar body weights. Week 16 efficacy parameters, including Investigator's Global Assessment score 0/1, greater than or equal to 75% reduction from baseline in the Eczema Area and Severity Index (EASI), and percentage change from baseline in EASI and pruritus Numerical Rating Scale, generally increased with week 16 trough concentration; the plateau of these exposure-efficacy relationships occurred for most patients at exposures associated with the 300 mg q2w and 300 mg qw regimens. Japanese ethnicity did not remain in the population PK model as covariate with or without accounting for body weight differences. In Japanese and non-Japanese patients, efficacy responses increased with week 16 dupilumab trough concentrations in a similar manner. Dupilumab 300 mg qw and q2w regimens were recommended for further evaluation in larger phase III studies.

The Posology of Dupilumab in Pediatric Patients With Atopic Dermatitis.

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response (E-R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non-weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E-R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment-emergent conjunctivitis. Based on these analyses, a weight-tiered posology was proposed for adolescents (200/300 mg q2w in patients 30-< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15-< 30 kg, 200 mg q2w in patients 30-< 60 kg) with moderate-to-severe AD.

Base and Covariate Population Pharmacokinetic Analyses of Dupilumab in Adolescents and Children ≥6 to <12 Years of Age Using Phase 3 Data.

Population pharmacokinetic (PK) base and covariate analyses were conducted using data from adolescents with moderate-to-severe atopic dermatitis (AD) and children ≥6 to <12 years of age with severe AD. Two phase 3 studies were analyzed (165 adolescents and 241 children on active treatment). A 2-compartment model with linear and Michaelis-Menten elimination and 3 transit compartments describing lag time in absorption was utilized. Weight, albumin, body mass index, and Eczema Area and Severity Index score were statistically significant covariates in at least 1 of the age populations. Only body weight had a consequential effect on central volume. Although an absorption rate and target-mediated clearance somewhat decreased with age, no dose adjustment was needed in addition to the adjustment for weight already implemented in the phase 3 studies. Otherwise, population PK parameters and covariates were similar across the 2 pediatric subpopulations and in adults. No allometric changes in elimination rate and beta half-life were observed with weight. Parameterization of models in terms of rates was a useful alternative to parameterization in terms of clearances, allowing for an absence of repeated covariates and preventing overparameterization. The model adequately described dupilumab pharmacokinetics in the pediatric populations.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Population Pharmacodynamic Model of Neutrophil Margination and Tolerance to Describe Effect of Sarilumab on Absolute Neutrophil Count in Patients with Rheumatoid Arthritis.

Evidence suggests that effects of interleukin-6 pathway inhibitors sarilumab, tocilizumab, and sirukumab on absolute neutrophil count (ANC) are due to margination of circulating neutrophils into rapidly mobilizable noncirculating pools. We developed a population pharmacodynamic model using compartments for neutrophil margination and ANC-specific tolerance to describe rapid, transient ANC changes in blood following administration of subcutaneous sarilumab and intravenous/subcutaneous tocilizumab based on data from 322 patients with rheumatoid arthritis in two single-dose (NCT02097524 and NCT02404558) and one multiple-dose (NCT01768572) trials. The model incorporated a tolerance compartment to account for ANC nadir and beginning of recovery before maximal drug concentration after subcutaneous dosing, and absence of a nadir plateau when the ANC response is saturated after subcutaneous or intravenous dosing. The model effectively describes the ANC changes and supports neutrophil margination and tolerance as an explanation for the absence of increased infection risk associated with low ANC due to interleukin-6 pathway inhibitor treatment.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects.

Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor α subunit (IL-4Rα) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4Rα-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.

Base and Covariate Population Pharmacokinetic Analyses of Dupilumab Using Phase 3 Data.

Population pharmacokinetic base and covariate models were developed to study functional dupilumab for regulatory submissions, using data from healthy volunteers and patients with moderate-to-severe atopic dermatitis (AD) receiving intravenous or subcutaneous doses. Sixteen studies were pooled (N = 2115; 202 healthy volunteers, 1913 AD patients). The best model was a 2-compartment model with linear and Michaelis-Menten elimination and 3 transit compartments describing absorption. A stepwise approach to model building, with some parameters estimated using mostly rich data and subsequently fixed, was used to avoid adverse effects of sparse data and a steep target-mediated phase on pharmacokinetic parameters, which require rich sampling for proper estimation. Parameterization of models in terms of rates was a useful alternative to the parameterization in terms of clearances, allowing for a reduced number of covariates while providing accurate predictions. While antidrug antibodies, albumin, race, body mass index, and Eczema Area and Severity Index score were statistically significant covariates, only body weight had a notable effect on central volume, explaining interindividual variability. The model adequately described dupilumab pharmacokinetics in phase 3 trials.

Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer.

The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade.

Periglomerular accumulation of dendritic cells in rat crescentic glomerulonephritis.

BACKGROUND: An increased number of major histocompatibility complex (MHC) class II-positive cells (OX-6+ cells) were observed in the glomerulus and periglomerular interstitium during the course of anti-glomerular basement membrane (anti-GBM) crescentic glomerulonephritis (GN) in WKY rats. This study aimed to demonstrate that periglomerular OX-6+ cells are dendritic cells (DCs) and to clarify their roles in the pathogenesis of this GN. METHODS: Kidney sections were stained with the OX-6 and the rat DC marker OX-62 by immunohistochemistry, and periglomerular OX-6+ cells were observed by immunoelectron microscopy. Renal mRNA expression for CXCL12 was examined by reverse transcriptase polymerase chain reaction (RT-PCR) and in situ hybridization, and that for IL-1beta was examined by in situ hybridization. RESULTS: Immunohistochemistry revealed that most periglomerular OX-6+ cells in this GN were ED-1-negative. OX-62+ cells were observed sparsely in normal kidney interstitium, and considerably more frequently in periglomerular interstitium in this GN. Immunoelectron microscopy confirmed the periglomerular OX-6+ED-1- cells had DC morphology. The increased expression of CXCL12 mRNA in the diseased glomerulus was shown by RT-PCR. By in situ hybridization, CXCL12 mRNA-expressing glomerular cells were the parietal and visceral epithelial cells, which were close to the site of periglomerular OX-6+ cell localization. The intense expression of IL-1beta mRNA by periglomerular cells was demonstrated by in situ hybridization. CONCLUSIONS: The periglomerular distribution of OX-6+ED-1- DCs was demonstrated in anti-GBM crescentic GN in WKY rats. These DCs might be accumulated in periglomerular interstitium by CXCL12, and play a role in the initiation and progression of this GN by producing IL-1beta.

Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats.

BACKGROUND: A crucial role for CD8(+) cells in induction of crescentic anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in WKY rats was demonstrated in studies showing that depletion of CD8(+) cells completely suppressed glomerular accumulation of monocytes/macrophages (Mo/Mphi), crescent formation and proteinuria. Because these studies did not definitively identify CD8(+) cells as the cause of tissue injury, we examined the roles of Mo/Mphi in the development of anti-GBM GN. METHODS: We examined correlations between the amount of urinary protein and the numbers of glomerular CD8(+) cells or Mo/Mphi in rats after administrating different doses of anti-GBM antibody (5.0, 7.5, 10.0 and 25.0 microl/100 g body weight). The roles of Mo/Mphi in induction of GN were examined in animals by depleting Mo/Mphi in the glomerulus. To do this, rats were injected intravenously with liposome-encapsulated dichloromethylene diphosphonate (liposome-MDP) from day 3 to day 7 after anti-GBM antibody injection and they were then sacrificed at day 8. RESULTS: Liposome-MDP treatment significantly reduced the number of ED-1(+) Mo/Mphi accumulated in glomeruli from 32.1 +/- 1.2 to 1.4 +/- 0.3/glomerular cross-section (mean +/- SD, P < 0.01), and the amount of urinary protein from 103.8 +/- 19.8 to 31.8 +/- 15.9 mg/day (P < 0.01), as well as the incidence of crescentic glomeruli from 91.3 +/- 2.7 to 23.3 +/- 7.6% (P < 0.01) at day 8. This treatment also reduced the number of CD8(+) cells accumulating in the glomeruli from 5.4 +/- 0.7 to 0.5 +/- 0.1/glomerular cross-section (P < 0.01). Upregulation of glomerular intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) mRNA expression was suppressed by Mo/Mphi depletion. CONCLUSION: These results indicate that Mo/Mphi play an important role in the induction of crescentic anti-GBM GN and glomerular injury.

Expression of MMP-9 in mesangial cells and its changes in anti-GBM glomerulonephritis in WKY rats.

BACKGROUND: Matrix metalloproteinase (MMP)-9, a member of the MMP family with specificity towards type IV collagen, is implicated in the turnover of the extracellular matrix in the kidney. To elucidate its physiological and pathophysiological significance, we examined the expression and localization of MMP-9 in the normal kidney and the changes in these features during the course of anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats, along with the changes in these features of tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2. METHODS: The expression of MMP-9, TIMP-1 and MMP-2 mRNA was quantified by ribonuclease protection assay, and the gelatinolytic activities of MMP-9 and MMP-2 were evaluated by gelatin zymography. The localization of MMP-9 was visualized by immunohistochemistry and immunofluorescence microscopy. RESULTS: The ribonuclease protection assay indicated the almost exclusive expression of MMP-9 mRNA in the glomerulus of normal kidneys. Immunohistochemistry and double-label immunofluorescence microscopy showed that MMP-9 was localized in the mesangial cells. During the course of anti-GBM glomerulonephritis, the expression of MMP-9 mRNA in glomeruli increased on day 1, peaked on days 3 to 7, and then decreased on day 14. The change in MMP-9 mRNA expression was accompanied by parallel changes in the gelatinolytic activity of the active form of MMP-9, TIMP-1 mRNA expression, and MMP-9 immunoreactivity in mesangial cells. In contrast, glomerular MMP-2 mRNA expression and its activity increased after the decline of MMP-9. CONCLUSIONS: MMP-9 mRNA was predominantly expressed in the glomerulus in normal rat kidneys and MMP-9 was present in the mesangium. The MMP-9 mRNA expression increased in the glomerulus 3 to 7 days after the induction of anti-GBM glomerulonephritis in WKY rats, in parallel with the development of abnormal glomerular histology and injury, suggesting a role of MMP-9 in proteolysis of the GBM during glomerulonephritis. MMP-2 may participate in the later phase of the nephritis.

Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats.

Anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats is characterized by glomerular accumulation of CD8(+) T cells and monocytes/macrophages, followed by crescent formation. The mechanism of leukocyte accumulation after antibody binding to GBM is still unclear. To unveil an involvement of Fcgamma receptors (FcgammaR) in leukocytes recruitment we examined the expression of FcgammaR in glomeruli and the effects of the administration of F(ab')(2) fragment of anti-GBM antibody or FcgammaR blocking on the initiation and progression of this model. A gradual increase of FcgammaR mRNA expression in glomeruli during the time course of disease suggested their significance in the development of glomerulonephritis. Glomerular lesions and proteinuria were induced only in rats injected with intact IgG of anti-GBM antibody, but not with the F(ab')(2) fragment. In vivo blocking of FcgammaR by administering heat-aggregated IgG led to the decrease of mRNA expression for all types of FcgammaR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcgammaR2-expressing cells in glomeruli were identified as macrophages, but not CD8(+) T cells. The expression of FcgammaR1 and 3 was significantly decreased, and that of FcgammaR2 became undetectable in CD8(+) T cell-depleted rats. Thus, CD8(+) T cells may stimulate FcgammaR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc-FcgammaR interaction in glomerular recruitment of macrophages and following induction of anti-GBM glomerulonephritis in WKY rats.

Suppression of experimental crescentic glomerulonephritis by interleukin-10 gene transfer.

BACKGROUND: Investigated were effects of overexpression of interleukin-10 (IL-10) on the outcome and progression of crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. METHODS: Rats were singly or simultaneously injected with antiglomerular basement membrane (a-GBM) antibody and adenoviral vector encoding rat IL-10 (Ad-rIL-10) or LacZ (Ad-LacZ) (3 x 1010 pfu/rat) intravenously, and were sacrificed at day 7. Their kidneys and other organs were isolated and examined by histology and immunohistochemistry. The In vivo expression of IL-10 mRNA in the liver of Ad-rIL-10-injected rats was confirmed by both reverse transcription-polymerase chain reaction (RT-PCR) and ribonuclease protection assay analysis and its translated protein was measured in the serum by enzyme-linked immunosorbent assay (ELISA). RESULTS: The exogenous IL-10 mRNA was strongly expressed in the liver in a dose-dependent manner and was intense at days 4 and 7 but was less intense at day 14. Ad-rIL-10 treatment significantly reduced the incidence of glomerular crescent formation from 67%+/- 1.9% in a-GBM antibody-treated group or 69.8%+/- 1.9% in a-GBM antibody + Ad-LacZ-treated group to 21.6%+/- 1.8% (P < 0.001), the glomerular infiltration of macrophages from 35.7 +/- 6.3 cell s/gcs (a-GBM antibody) or 37.6 +/- 8.6 cells/gcs (both a-GBM antibody + Ad-LacZ) to 17.9 +/- 5.5 cells/gcs (P < 0.001), that of major histocompatibility complex (MHC) class II-positive cells from 14.4 +/- 5.3 cells/gcs (a-GBM antibody) or 15 +/- 4.6 cells/gcs (a-GBM antibody + Ad-LacZ) to 5.7 +/- 2.3 cells/gcs (P < 0.0001) at day 7, the glomerular and immune tissue expression of IL-1beta mRNA, as well as the proteinuria from 159.0 +/- 22.7 mg/24 hours (a-GBM antibody) or 166 +/- 28 mg/24 hours (a-GBM antibody + Ad-LacZ) to 42.2 +/- 35.2 mg/24 hours (P < 0.01) at day 7. The serum creatinine and blood urea nitrogen levels were also reduced from 2.8 +/- 0.1 mg/dL (a-GBM antibody) or 2.8 +/- 0.1 mg/dL (a-GBM antibody + Ad-LacZ) to 1.0 +/- 0.1 mg/dL (P < 0.001) and from 63.2 +/- 8.9 mg/dL (a-GBM antibody) or 61.3 +/- 5.2 mg/dL (a-GBM antibody + Ad-LacZ) to 27.0 +/- 4.5 mg/dL (P < 0.001), respectively. However, the glomerular accumulation of CD8+ T cells was unaffected: 5.4 +/- 1.1 cells/gcs (a-GBM antibody + Ad-rIL-10), 5.9 +/- 1.5 cells/gcs (a-GBM antibody), and 5.8 +/- 1.1 cells/gcs (a-GBM antibody + Ad-LacZ) (P= NS). CONCLUSION: IL-10 gene transfer significantly attenuated the glomerular lesions and injury in the anti-GBM crescentic glomerulonephritis of WKY rats.

A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction.

BACKGROUND: Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor approved in >30 countries for the treatment of erectile dysfunction (ED). It has been shown to improve erectile function compared with placebo in Phase III studies, but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking. OBJECTIVE: This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED. It also compared the tolerability of the 2 agents at these doses. METHODS: This randomized, double-blind, fixed-dose, 2-period crossover trial took place at 13 sites in the United States and Germany. Patients were randomized 1:1 to receive 4 weeks of treatment with tadalafil 20 mg or sildenafil 50 mg, followed by the alternative treatment, to be taken as needed up to once daily before sexual activity. RESULTS: The study enrolled 215 men with ED, 109 randomized to the tadalafil-sildenafil sequence and 106 to the sildenafil-tadalafil sequence. Their mean age was 49.8 years; 84.7% were sildenafil naive and 15.3% had undergone a previous inadequate trial of sildenafil. Most patients had moderate ED (60.5%) of >or=1 year's duration (74.9%). Of 190 evaluable patients, 126 (66.3%) preferred to initiate treatment with tadalafil, compared with 64 (33.7%) with sildenafil (P < 0.001). Patients' preference did not differ by age, duration of ED, treatment sequence, or previous sildenafil exposure. Both medications were well tolerated, with no significant differences in the incidence of treatment-emergent adverse events. Headache (11.2% tadalafil, 8.8% sildenafil), dyspepsia (6.0% and 4.2%, respectively), nasopharyngitis (4.7% and 2.8%), and flushing (2.8% and 4.7%) were the most common adverse events. The rate of ocular disturbances was low: 1 patient experienced intermittent bilateral reduction in visual acuity with tadalafil, and 2 exhibited conjunctival hyperemia or eyelid edema with sildenafil. CONCLUSIONS: Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population. Both medications were well tolerated.

Factors associated with adolescent utilization of alcohol treatment services.

OBJECTIVE: This study examined factors associated with adolescents' use of alcohol treatment services. METHOD: Data on adolescents (aged 12-17) from the 1994 National Household Survey on Drug Abuse (NHSDA, N = 4,698), a large representative sample of the U.S. population, were used in this study. Information obtained from the survey included adolescent alcohol use, drinking patterns, alcohol abuse/dependent problems, and service use for alcohol-related problems. In addition, socio- demographics, health insurance, mental and behavioral problems, and other drug use were also included in the analysis. RESULTS: The findings indicate that many adolescents with alcohol problems did not receive treatment. White adolescents were more likely to receive alcohol treatment services than nonwhites. Among alcohol-related problems, alcohol causing problems at home, school, or other settings predicted entry into alcohol treatment. Drug use and poor health status were also associated with receiving alcohol treatment services. CONCLUSIONS: This study calls for an improved service delivery system to meet service needs of adolescents with alcohol-related problems, especially among minorities, and those with alcohol-related problems but without yet experiencing significant negative social consequences.