Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study.

AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite-Resolution for Clinical Development.

Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [14C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [14C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.

A phase 2 study of simtuzumab in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis.

Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose-proportionally between the 200-mg and 700-mg treatment groups. Therapy-related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700-mg group, 1 (6·7%) in the simtuzumab 200-mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700-mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

Exclusion of a luminous red giant as a companion star to the progenitor of supernova SN 2011fe.

Type Ia supernovae are thought to result from a thermonuclear explosion of an accreting white dwarf in a binary system, but little is known of the precise nature of the companion star and the physical properties of the progenitor system. There are two classes of models: double-degenerate (involving two white dwarfs in a close binary system) and single-degenerate models. In the latter, the primary white dwarf accretes material from a secondary companion until conditions are such that carbon ignites, at a mass of 1.38 times the mass of the Sun. The type Ia supernova SN 2011fe was recently detected in a nearby galaxy. Here we report an analysis of archival images of the location of SN 2011fe. The luminosity of the progenitor system (especially the companion star) is 10-100 times fainter than previous limits on other type Ia supernova progenitor systems, allowing us to rule out luminous red giants and almost all helium stars as the mass-donating companion to the exploding white dwarf.

Supernova SN 2011fe from an exploding carbon-oxygen white dwarf star.

Type Ia supernovae have been used empirically as 'standard candles' to demonstrate the acceleration of the expansion of the Universe even though fundamental details, such as the nature of their progenitor systems and how the stars explode, remain a mystery. There is consensus that a white dwarf star explodes after accreting matter in a binary system, but the secondary body could be anything from a main-sequence star to a red giant, or even another white dwarf. This uncertainty stems from the fact that no recent type Ia supernova has been discovered close enough to Earth to detect the stars before explosion. Here we report early observations of supernova SN 2011fe in the galaxy M101 at a distance from Earth of 6.4 megaparsecs. We find that the exploding star was probably a carbon-oxygen white dwarf, and from the lack of an early shock we conclude that the companion was probably a main-sequence star. Early spectroscopy shows high-velocity oxygen that slows rapidly, on a timescale of hours, and extensive mixing of newly synthesized intermediate-mass elements in the outermost layers of the supernova. A companion paper uses pre-explosion images to rule out luminous red giants and most helium stars as companions to the progenitor.

Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas.

Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing.

Population pharmacokinetics of intramuscular recombinant Erwinia chrysanthemi asparaginase (JZP458) in patients with acute lymphoblastic leukemia.

JZP458 is a recombinant Erwinia chrysanthemi asparaginase for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who have developed hypersensitivity to Escherichia coli-derived asparaginases. A population pharmacokinetic (PopPK) model was developed for intramuscular (i.m.) JZP458 using serum asparaginase activity (SAA) data from 166 patients with ALL/LBL enrolled in a phase II/III study conducted in collaboration with the Children's Oncology Group (AALL1931; NCT04145531). The pharmacokinetics of i.m. JZP458 is best characterized by a one-compartment model with mixed-order absorption and linear elimination, with body surface area included as an allometric covariate on JZP458 SAA clearance and volume, and race (i.e., Black/African American) and disease subtype (i.e., T-cell ALL) as covariates on JZP458 SAA clearance. The PopPK model was used to simulate SAA profiles to estimate the likelihood of achieving nadir SAA (NSAA) levels greater than or equal to 0.1 IU/mL with different dosing regimens. Model-based simulations suggest when JZP458 is administered i.m. at 25/25/50 mg/m2 Monday/Wednesday/Friday (MWF), 92.1% of subjects (95% confidence interval [CI]: 90.9%, 93.3%) are expected to achieve the last 72-h (after 50 mg/m2 dose) NSAA level greater than or equal to 0.1 IU/mL, and 93.8% (95% CI: 92.7%, 94.9%) are expected to achieve the last 48-h (after 25 mg/m2 dose) NSAA level greater than or equal to 0.1 IU/mL. When JZP458 is administered 25 mg/m2 i.m. every 48 h, 93.8% (95% CI: 92.7%, 94.8%) are expected to achieve the last 48-h NSAA level greater than or equal to 0.1 IU/mL. These data supported the i.m. dose of 25 mg/m2 every 48 h or 25/25/50 mg/m2 on a MWF dosing schedule in patients with ALL/LBL.

Mobile technologies: a powerful force in home care.

Mobile and wireless technologies are rapidly changing how home care is delivered and operationalized. "mHealth," or mobile health, in general, refers to healthcare practice that is supported by mobile devices, such as mobile phones, personal digital assistants (PDAs), and other wireless devices.

Structure-activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists.

This letter describes the structure-activity relationship (SAR) of the 'right-wing' α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved.

Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP-458).

JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross-reactivity to Escherichia coli-derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli-derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP-458 using serum asparaginase activity (SAA) data from a phase 1, single-dose study (JZP458-101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP-458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP-458: intramuscular (IM) data at 12.5 mg/m2 (N = 6) and 25 mg/m2 (N = 6), and intravenous (IV) data at 25 mg/m2 (N = 6) and 37.5 mg/m2 (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP-458 is expected to achieve 72-hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m2 , and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m2 on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m2 IM or 37.5 mg/m2 IV on a M/W/F dosing schedule in pediatric and adult patients.

A Randomized Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Recombinant Erwinia Asparaginase (JZP-458) in Healthy Adult Volunteers.

L-asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 40 years, and is standard therapy during ALL induction and consolidation treatment. L-asparaginases are immunogenic and can induce hypersensitivity reactions; inability to receive asparaginase has been associated with poor patient outcomes. There are L-asparaginases of varied bacterial origins, with the most commonly used being Escherichia coli (E. coli); therefore, to ensure that patients who develop hypersensitivity to E. coli-derived asparaginases receive an adequate therapeutic course, alternative preparations are warranted. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli-derived asparaginases. To evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP-458, a randomized, single-center, open-label, phase I study was conducted with JZP-458 given via i.m. injection or i.v. infusion to healthy adult volunteers. At the highest doses tested for each route of administration (i.e., 25 mg/m2 i.m. and 37.5 mg/m2 i.v.), JZP-458 achieved serum asparaginase activity (SAA) levels ≥ 0.1 IU/mL at 72 hours postdose for 100% of volunteers. Bioavailability for i.m. JZP-458 was estimated at 36.8% based on SAA data. All dose levels were well-tolerated, with no unanticipated adverse events (AEs), no serious AEs, and no grade 3 or higher AEs. Based on PK and safety data, the recommended JZP-458 starting dose for the pivotal phase II/III study in adult and pediatric patients is 25 mg/m2 i.m. and 37.5 mg/m2 i.v. on a Monday/Wednesday/Friday dosing schedule.

Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Metabolism of (+)-1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595), a novel replication-dependent DNA-damaging agent.

(+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595 or AG-7352) is currently under investigation for the treatment of platinum-resistant ovarian cancer and acute myeloid leukemia. In vitro voreloxin undergoes minimal cytochrome P450 (P450) and UDP glucuronosyltransferase (UGT)-mediated metabolism, and in vivo excretion of unchanged voreloxin as the major species is consistent with the slow rate of metabolism observed in vitro. The objective of the present study was to examine the cross-species metabolic profile of voreloxin and to identify and characterize the metabolites formed in rats. We also investigated baculovirus-expressed human P450s and UGTs to determine which isoforms participated in voreloxin metabolism. Incubations using human, monkey, and rat liver microsomes showed monkey and rat metabolism is similar to human. Voreloxin and metabolites collected from plasma, bile, and urine from rats administered radiolabeled voreloxin were separated by high-performance liquid chromatography, and their structures were elucidated by liquid chromatography/tandem mass spectrometry. Activity of metabolites was determined with authentic reference standards in cell-based cytotoxicity assays. The proposed structures of metabolites suggest that metabolic pathways for voreloxin include glucuronide conjugation, oxidation, N-dealkylation, and O-dealkylation.

Water-soluble prodrugs of an Aurora kinase inhibitor.

Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.

2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

Interaction of SN Ib 2004dk with a Previously Expelled Envelope.

The interaction between the expanding supernova (SN) ejecta with the circumstellar material (CSM) that was expelled from the progenitor prior to explosion is a long-sought phenomenon, yet observational evidence is scarce. Here we confirm a new example: SN 2004dk, originally a hydrogen-poor, helium-rich Type Ib SN that reappeared as a strong Hα-emitting point source on narrowband Hα images. We present follow-up optical spectroscopy that reveals the presence of a broad Hα component with full width at half maximum of ~ 290 km s-1 in addition to the narrow Hα+[N ii] emission features from the host galaxy. Such a broad component is a clear sign of an ejecta-CSM interaction. We also present observations with the XMM-Newton Observatory, the Swift satellite, and the Chandra X-ray Observatory that span 10 days to 15 years after discovery. The detection of strong radio, X-ray, and Hα emission years after explosion allows various constraints to be put on pre-SN mass-loss processes. We present a wind-bubble model in which the CSM is "pre-prepared" by a fast wind interacting with a slow wind. Much of the outer density profile into which the SN explodes corresponds to no steady-state mass-loss process. We estimate that the shell of compressed slow wind material was ejected ~1400 yr prior to explosion, perhaps during carbon burning, and that the SN shock had swept up about 0.04 M ⊙ of material. The region emitting the Hα has a density of order 10-20 g cm-3.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Hemoglobin köln and pregnancy.

BACKGROUND: Patients with hemoglobin Köln usually present with a mild hemolytic anemia characterized by reticulocytosis, splenomegaly, and elevated circulating bilirubin and lactate dehydrogenase levels. There have been no previous reports of whether these characteristics change during pregnancy and whether pregnancy provides any specific concerns for patients with hemoglobin Köln. CASE: A 36-year-old woman of Chinese origin with a twin pregnancy had an uneventful antenatal course except for the presence of thrombocytopenia that was not completely investigated. During elective repeat Caesarean section, it was noted that the woman had a low SpO2 on pulse oximetry despite a normal arterial oxygen tension from arterial blood gas measurement. Subsequent investigations identified the woman as a heterozygous carrier for hemoglobin Köln. CONCLUSION: Women with hemoglobin Köln who become pregnant require close monitoring of the maternal platelet count and an awareness of the falsely low SpO2 on pulse oximetry to ensure a favourable outcome.

Pharmacokinetics and Safety of Momelotinib in Subjects With Hepatic or Renal Impairment.

Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to ∞ [AUC∞ ] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC∞ was increased (GMR, 197%; 90%CI, 129%-301%), and M21 AUC∞ was decreased (GMR, 52%; 90%CI, 34%-79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced.

The Drug-Drug Interaction Profile of Presatovir.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUCinf ), and decreased by rifampin (40.3% in Cmax and 82.5% in AUCinf ) and efavirenz (55.7% in AUCinf ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.