Changes In Absolute Neutrophil Counts Research Articles

Change in absolute neutrophil count after COVID-19 infection in patients using clozapine versus other antipsychotics.

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.

Baseline Circulating Blood Cell Counts and Ratios and Changes Therein for Predicting Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy: A Multicenter, Prospective, Observational, Pan-Cancer Cohort Study with a Gender Perspective.

Several factors have been associated with the occurrence of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy. Despite their availability, the predictive value of circulating blood cell parameters remains underexplored. Our aim was to investigate whether baseline values of and early changes in absolute neutrophil count (ANC), absolute lymphocyte count (ALC), other blood cell counts, and lymphocyte-related ratios can predict irAEs and whether sex may differentially influence this potential predictive ability. Of the 145 patients included, 52 patients (35.8%) experienced at least one irAE, with a 1-year cumulative incidence of 41.6%. Using Fine and Gray competing risk models, we identified female sex (hazard ratio (HR) = 2.17, 95% confidence interval (CI) = 1.20-3.85), high ALC before ICI initiation (HR = 1.63, 95% CI = 1.09-2.45), and low ANC after ICI initiation (HR = 0.81, 95% CI = 0.69-0.96) as predictors of irAEs. However, ALC and ANC may only have an impact on the risk of irAEs in women (stratified for female sex, ALC-related HR = 2.61, 95% CI = 1.40-4.86 and ANC-related HR = 0.57, 95% CI = 0.41-0.81). Priority should be given to developing models to predict ICI-related toxicity and their validation in various settings, and such models should assess the impact of patient sex on the risk of toxicity.

Immunogenicity of Sarilumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant to Disease-Modifying Antirheumatic Drugs.

IntroductionThis open-label study evaluated the immunogenicity, safety, and efficacy of sarilumab monotherapy in patients with active, moderate-to-severe rheumatoid arthritis (RA) and inadequate response or intolerance to prior conventional synthetic disease-modifying antirheumatic drugs.MethodsAdults with RA (n = 132) were randomized to receive subcutaneous sarilumab (150 [n = 65] or 200 mg [n = 67]) every 2 weeks (q2w) for 24 weeks. Endpoints included incidence of antidrug antibodies (ADAs) at week 24, safety, and efficacy.ResultsPersistent ADAs occurred in eight patients (12.3%) receiving sarilumab 150 mg q2w, seven of whom (10.8%) had neutralizing antibodies (NAbs), and in four patients (6.1%) receiving sarilumab 200 mg q2w, two of whom (3.0%) had NAbs; all exhibited low antibody titers. Infections and neutropenia were the most common adverse events (AEs). There were three serious AEs, no reports of anaphylaxis, and few hypersensitivity reactions (e.g., rash) with no notable differences in hypersensitivity reactions in ADA-positive patients relative to ADA-negative patients. Changes in absolute neutrophil count, alanine aminotransferase level, and platelet count were consistent with interleukin-6 signaling blockade and in agreement with previous observations. At week 24, overall American College of Rheumatology 20%/50%/70% improvement criteria responses were 73.8%/53.8%/29.2%, respectively, with sarilumab 150 mg q2w and 71.6%/50.7%/29.9% with sarilumab 200 mg q2w. No patients with an ADA-positive response showed loss of efficacy.ConclusionsADA titers were low and persistent ADAs and NAbs occurred relatively infrequently in both sarilumab dose groups. ADA did not meaningfully impact the safety or efficacy of either dose of sarilumab over 24 weeks.Trial RegistrationClinicalTrials.gov, identifier NCT02121210.FundingSanofi Genzyme and Regeneron Pharmaceuticals, Inc.Plain Language SummaryPlain language summary available for this article.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-019-0157-3) contains supplementary material, which is available to authorized users.

The prognostic value of haematologic parameter changes during treatment in cervical cancer patients treated with definitive chemoradiotherapy

We retrospectively analysed the prognostic significance of changes in absolute neutrophil count (ANC), absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) during treatment with definitive chemoradiotherapy (CRT) in 104 cervical cancer patients. The absolute white blood cell, ANC and ALC decrease during treatment, NLR increased throughout treatment and reached to a plateau at fifth week. The ANC and NLR after 3rd week of definitive CRT were significantly higher and ALC after 3rd week of treatment was significantly lower in patients with progressive disease compared patients with no evidence of disease. Patients in low-haematological risk (LHR) group had significantly higher number of patients with smaller tumour size, early stage disease and without lymph node metastasis. In multivariate analysis, high-haematological risk (HHR) group and lymph node metastasis were negative prognosticators of overall and disease-free survival (DFS). The presence of lymph node metastasis and HHR could serve as a predicative factor of poor prognosis for cervical cancer patients. IMPACT STATEMENT What is already known on this subject? The ANC and NLR after 3rd week of definitive CRT were significantly higher and ALC after 3rd week of treatment was significantly lower in patients with progressive disease compared patients with no evidence of disease. Patients in LHR group had significantly higher number of patients with smaller tumour size, early stage disease and without lymph node metastasis. Lymph node metastasis and HHR and were negative prognosticators of overall and disease-free survival (DFS). The presence of lymph node metastasis and HHR could serve as a predicative factor of poor prognosis for cervical cancer patients. What the results of this study add? Weekly changes in ANC, ALC, and NLR, especially after 3rd week of treatment are predictive factors of disease progression, not the high-risk features of disease. Furthermore, in HHR group more patients with extensive stage disease, larger tumour and lymph node metastasis were observed compared to LHR group. What the implications are of these findings for clinical practice and/or further research? The patients may be stratified according to risk factors. The treatment intensification maybe required for HHR patients compared to LHR patients. Since our findings are preliminary, further studies are required to support these findings.

What is the Role of Race and Ethnicity in the Development Of Thionamide-Induced Neutropenia?

Thionamides are anti-thyroid drugs (ATD) used to treat autonomous thyrotoxicosis. Although efficacious, these medications carry a risk of neutropenia or agranulocytosis. Some risk factors for ATD-induced neutropenia have been identified, including dose, age, and female sex, but the role of race and ethnicity has not been well studied. We hypothesize that there will be no effect of race or ethnicity on the change in Absolute Neutrophil Count (ANC) following initiation of ATD therapy. Data from the Electronic Medical Record at UNM HSC were obtained using a standard database query. Inclusion criteria were the prescription of an ATD, an ANC recorded within 30 days of initiating ATD therapy (Pre-ATD), and an ANC recorded 75 - 365 days after starting an ANC (Post-ATD). Patients taking other agents known to cause neutropenia were excluded. Racial and ethnic groups were assigned as follows: Hispanic, Non-Hispanic White, Native American, Black/African American, and Asian/Pacific Islander. Post-ATD ANC was defined as the nadir ANC after ATD initiation. "Delta ANC" was defined as ((Post-ATD ANC) - (Pre-ATD ANC)). ANOVA analysis with Bonferroni-adjusted post-hoc testing and multiple regression were performed to examine differences in the mean changes in ANC across ethnic groups. One hundred and twenty-three adult patients met inclusion and exclusion criteria and were included in the analysis. The Native American group showed a significantly greater Post-ATD ANC and Delta-ANC as compared to the other groups (p<0.001). In this cohort of New Mexicans with thyrotoxicosis, Native American race was protective against thionamide-induced neutropenia.

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OBJECTIVES/SPECIFIC AIMS: Thionamides are anti-thyroid drugs (ATD) that are commonly used to treat autonomous thyrotoxicosis. Although efficacious, these medications carry a risk of neutropenia or agranulocytosis in a small but finite proportion of the patients who receive them. Some risk factors for thionamide-induced neutropenia have been identified, including body mass index (BMI) and dose, but the role of race and ethnicity in the pathogenesis of this potentially life-threatening side effect is not known. We hypothesize that there will be no effect of race or ethnicity on the change in absolute neutrophil count (ANC) following initiation of thionamide therapy among adult patients with thyrotoxicosis. METHODS/STUDY POPULATION: Data from the electronic medical record at UNM HSC were obtained using a standard database query for the years 2000–2016. Inclusion criteria were the prescription of an ATD, an ANC recorded within 30 days of initiating ATD therapy (pre-ATD), and an ANC recorded between 75 and 365 days after starting an ANC (post-ATD). Patients taking other agents known to cause neutropenia and agranulocytosis, such as clozapine, allopurinol, or chemotherapy, were excluded. Patients were assigned to racial and ethnic groups as follows: Hispanic, non-Hispanic Caucasian (NHC), native American, Black, and Asian. The post-ATD ANC was defined as the nadir ANC observed after the ATD was started. “Delta ANC” was defined as [(post-ATD ANC)−(pre-ATD ANC)]. ANOVA analysis with Bonferroni-adjusted post-hoc testing was performed to examine differences in the mean changes of ANC across ethnic groups. RESULTS/ANTICIPATED RESULTS: In total, 123 adult patients met inclusion and exclusion criteria and were included in the analysis. No significant difference was found between any of the racial groups with regard to age, sex, BMI, pre-ATD ANC, or the pre-ATD to post-ATD ANC interval. The native American group showed a significantly greater post-ATD ANC (not shown) and Delta-ANC as compared with the other groups. Delta ANC Hispanic=−1.4±3.3, Caucasian=−0.6±3.3, Black=−0.9±4.1, Asian=−3.8±4.8, native American=3.6±5.1 (all units per mm3; p&lt;0.001). DISCUSSION/SIGNIFICANCE OF IMPACT: In this cohort of New Mexicans with thyrotoxicosis, native American race was protective against thionamide-induced neutropenia.

Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial

Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial

A Proposed Steroid Mobilization Test to Separate Margination From Marrow Suppression and to Determine Drug Cessation for Safety in Lenalidomide-Induced Neutropenia in Non-Del(5q) MDS Low and INT-1 Patients

AbstractAbstract 4942 BackgroundThe mechanism of lenalidomide-induced neutropenia, a common reason for cessation of therapy, has recently been shown to involve down-regulation of transcription factor PU. 1, resulting in granulocyte maturation arrest and accumulation of myeloid precursors (Pal S, et al. Blood 2010; 115(3):605–614). Data have also exhibited a correlation between cytopenias and response to therapy in del(5q) patients alone, revealing lenalidomide-induced neutropenia or thrombocytopenia as a predictor of transfusion independence (Sekeres MA, et al. J Clin Oncol 2008. 26(36):5943–5949). Because preliminary data from our phase I/II optimal dose study in non-5q- low and int-1 risk patients has shown a lower degree of both neutropenia and thrombocytopenia than that observed in patients treated with the same 10mg/d dose for del(5q) disease, we hypothesized that the comparably poor response of non-del(5q) patients may be related to the lesser degree of associated cytopenias in the setting of a suboptimal dose. Anticipating the limitation of optimal dosing by neutropenias, we set out to determine whether we could avoid withholding the drug for safety by demonstrating the patients’ ability to mobilize neutrophils with corticosteroid administration, in contrast to limitation by true marrow suppression. MethodsIn the course of our phase I/II optimal dose study, we examined whether cytopenias observed with high dose lenalidomide may be attributed to margination rather than entirely to true marrow suppression. Eight patients with low or int-1 risk non-del(5q) MDS received lenalidomide at an increased dose of 15mg to 20mg, administered for 21d of each 28d cycle. A baseline absolute neutrophil count along with a pre-therapy response of peripheral granulocytes to prednisone was established. Patients whose absolute neutrophil count decreased during therapy to less than 50 percent of the pre-study baseline underwent a granulocyte mobilization test, receiving a 1mg/kg dose of prednisone with a complete blood count drawn both before and twenty four hours after administration to assess change in absolute neutrophil count. In patients with a positive steroid test, we proceeded with therapy. In those with a negative steroid test, lenalidomide was held until recovery of ANC. This study is listed on clinicaltrials. gov under the identifier NCT00699842. ResultsOf the 8 patients enrolled in the study, 4 (50%) of these patients developed neutropenia with an absolute neutrophil count (ANC) falling to less than 50% of their pre-treatment baseline. Of these patients, 2 had a marked response to the prednisone granulocyte mobilization test, with 24-hour post-steroid ANC levels approaching and in most cases exceeding the patients' baseline values (Fig. 1). A third patient had a less notable and delayed response, but did exhibit an increase in ANC from less than 50% to within 5% of pre-study baseline. The fourth patient responded minimally and was taken off of the study to receive G-CSF (Fig. 3). [Display omitted] [Display omitted] [Display omitted] There was no increase in neutropenic fever during the course of the study, although the observation was limited to only 8 patients. ConclusionsDetermining increments of ANC (31000) following steroid administration in 3 (75%) of the studied patients who developed marked neutropenia in the setting of an elevated dose of lenalidomide demonstrated a return of the absolute neutrophil count to pre-treatment levels. The drug was continued on these patients with no neutropenic fever nor other adverse event. The results of the study provide evidence that margination of neutrophils is a contributing mechanism of lenalidomide-induced neutropenia, providing an alternative explanation to true marrow suppression as the primary etiology of observed cytopenias. This may allow for increased tolerance and determination of the optimal dose of lenalidomide in the treatment of patients with non-5q myelodysplastic syndrome. Disclosures:Besa:Celgene: Research Funding. Quan:Celgene: Employment.

Terminal Complement Inhibitor Eculizumab Improves Complement-Mediated Platelet Consumption and Thrombocytopenia in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Abstract 4030Poster Board III-966PNH is a hematopoietic stem cell disorder in which unregulated activation of the complement system leads to significant morbidities with shortened lifespan. Life threatening thromboembolism (TE) is the most feared complication of PNH, accounting for 45% of patient deaths. Approximately 40% of PNH patients experience a clinically evident TE and 60% of patients without clinically diagnosed TE demonstrate TE by high-sensitivity MRI, indicating the ongoing thrombotic risk in PNH patients. Thrombocytopenia is found in 25-50% of PNH patients at presentation. PNH platelets are extremely sensitive to terminal complement activation, and circulating platelets are activated in thrombocytopenic PNH patients without clinically diagnosed TE. Eculizumab, a monoclonal antibody targeted to complement C5, blocks the production of both C5a and C5b-9, and has been demonstrated to reduce TE events by up to 92% in PNH patients. Eculizumab has also been shown to beneficially impact several prothrombotic processes in PNH patients including hemolysis, nitric oxide consumption, thrombin generation, tissue factor pathways, and inflammation. We hypothesized that terminal complement activation of PNH platelets contributes to ongoing platelet activation, which is reflected by platelet consumption, contributing to chronic thrombocytopenia defined as platelets <100×109/L. This hypothesis was tested by examining whether chronic inhibition of terminal complement activation with eculizumab increases platelet counts in thrombocytopenic PNH patients. The study population was comprised of the 49 thrombocytopenic PNH patients identified from the total 195 patients in the SHEPHERD, TRIUMPH, and Phase 2 eculizumab trials. Platelet counts were measured at baseline, 26 and 52 weeks of eculizumab treatment. At baseline the median platelet count in the thrombocytopenic group was 68×109/L (range 23 to 97). Patients with thrombocytopenia were more likely to have a history of TE than patients with normal platelet counts (45% vs 27%; P<0.022). Treatment with eculizumab markedly inhibited terminal complement activity in all thrombocytopenic patients, as measured by a significant reduction in LDH at 26 and 52 weeks (median values at baseline, 26 weeks, and 52 weeks: 1746 IU/L, 290 IU/L, 286 IU/L, respectively, UNL 220 U/L); P<0.00001 for each time point vs. baseline). Chronic terminal complement inhibition with eculizumab significantly increased platelet counts to a non-thrombocytopenic level in 33% (95% CI: 20-48%) and 36% (95% CI: 22-51%) of thrombocytopenic patients at 26 and 52 weeks, respectively, of treatment. By inhibiting C5 activity, the median platelet counts significantly increased in thrombocytopenic patients from 68×109/L at baseline to 80 and 85×109/L (P<0.001) at 26 and 52 weeks, respectively. Eculizumab treatment significantly increased platelet counts in both thrombocytopenic patients with a history of TE and no history of TE (P<0.05 vs baseline in both groups). Treatment with eculizumab significantly increased platelet counts at 52 weeks in this thrombocytopenic patient population irrespective of a history of bone marrow failure (P<0.05 vs baseline for each group). As expected, there was no apparent impact of terminal complement inhibition on marrow blood cell production as measured by no change in absolute neutrophil count at 26 and 52 weeks. This suggests that the mechanism of platelet increase may be due to inhibition of terminal complement-mediated consumption of platelets in thrombocytopenic patients with PNH. The present study indicates that thrombosis in PNH patients is more frequent in patients with thrombocytopenia. Terminal complement deposition on PNH platelets results in platelet activation which in turn would be expected to result in platelet consumption, suggestive of a chronic prothrombotic state, in PNH patients. Earlier studies have shown that chronic terminal complement inhibition with eculizumab reduces thrombotic risk in patients with PNH. The current study shows that chronic terminal complement inhibition with eculizumab treatment improves pre-existing thrombocytopenia in a significant proportion of patients with PNH. These clinical findings warrant further investigation and suggest that terminal complement C5 activity contributes to platelet activation and consumption with subsequent thrombocytopenia and an increased thrombotic risk in patients with PNH. Disclosures:Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Höchsmann:Alexion: Honoraria. Hill:Alexion: Honoraria. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

ＩＦＬ療法によりｇｒａｄｅ ４の好中球減少が認められた大腸がん患者のＵＧＴ１Ａ１遺伝子多型と薬物体内動態解析

We carried out a pharmacogenetic analysis on uridine diphosphate glucuronosyltransferase (UGT)1A1 polymorphism and a pharmacokinetic analysis on irinotecan (CPT-11)and its metabolites for a patient who developed severe neutropenia after the first course of a CPT-11 (100 mg/m2),5-fluorouracil (5-FU) and leucovorin regimen (IFL regimen).Genotyping showed the patient to be homozygous for the UGT1A1*28 allele and heterozygous for UGT1A1*27 allele.In the pharmacokinetic analysis,the serum concentrations of CPT-11,SN-38,SN-38 glucuronide and 5-FU were measured.The AUC0-23.25h of SN-38 was 523.6 ng·h/mL at a dose of 32.5 mg/m2 of CPT-11,which was higher than that in the literature at a dose of 100 mg/m2.The serum concentration of 5-FU,however,was lower than that in the literature for the same dose.Lowering the dose of CPT-11 from 100 to 26 mg/m2 resulted in a decrease in CEA and CA 19-9 concentrations and a reduction in the lung metastatic focus.Considered together with the change in absolute neutrophil count observed,these findings suggested that the doses of CPT-11,5-FU and L-leucovorin be adjusted to 26 mg/m2,324 mg/m2 and 195 mg/m2 respectively and the washout period be extended.In conclusion,the UGT1A1 genetic analysis and follow-up monitoring of serum CPT-11 levels that we conducted facilitated the creation of a personalized IFL regimen for the patient,which improved efficacy and safety.

A Bayesian Population PK–PD Model of Ispinesib-induced Myelosuppression

The goal of the present analysis is to fit a Bayesian population pharmacokinetic pharmacodynomic (PK-PD) model to characterize the relationship between the concentration of ispinesib and changes in absolute neutrophil counts (ANC). Ispinesib, a kinesin spindle protein (KSP) inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. A first time in human, phase I open-label, non-randomized, dose-escalating study evaluated ispinesib at doses ranging from 1 to 21 mg/m(2). PK-PD data were collected from 45 patients with solid tumors. The pharmacokinetics of ispinesib were well characterized by a two-compartment model. A semimechanistic model was fit to the ANC. The PK and PD data were successfully modelled simultaneously. This is the first presentation of simultaneously fitting a PK-PD model to ANC using Bayesian methods. Bayesian methods allow for the use of prior information for some system-related parameters. The model may be used to examine different schedules, doses, and infusion times.

A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas

Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade gliomas in children. Myelosuppression (the suppression of bone marrow activity) is the dose-limiting toxicity for TMZ in adults and children. Empirical methods (i.e. relations between the percent change in absolute neutrophil count (ANC) and the area under the plasma concentration curve (AUC) of TMZ or its active metabolite MTIC) showed poor results when attempting to describe myelosuppression from serial data derived during TMZ therapy in a Phase II study of children with high-grade glioma. Therefore, to improve our understanding of the myelosuppressive effects of TMZ and MTIC in children we developed a mechanistic mathematical model. The model describes the progression of neutrophils from their production in the bone marrow to their release in the plasma. Included in the model are the feedback effects of granulocyte colony stimulating factor (G-CSF), which stimulates neutrophil production when there is a decrease in circulating neutrophils. The model is fit to serial ANC measurements obtained after TMZ dosing and it is able to explain, among other things, the lag in ANC reduction following a dose of TMZ, the ANC nadir, and the ‘rebound effect’ observed where the ANC recovers to levels greater than that observed pre-TMZ dose. This model will be useful for the prospective design of clinical trials of TMZ in children with cancer.

Neutrophil margination as a possible mechanism for verteporfin infusion-associated pain

Purpose To investigate the changes in absolute neutrophil counts in patients with and without pain after verteporfin infusion. Design Experimental study. Methods The absolute neutrophil counts were obtained from the blood samples taken at the beginning of infusion and after the end of verteporfin infusion. Results Four patients in whom verteporfin infusion-related pain developed had a decrease in the absolute neutrophil counts from a preinfusion mean of 4,589/mm 3 to a postinfusion mean of 1,688/mm 3 while they had pain, as compared with preinfusion and postinfusion counts of 4,912/mm 3 and 4,111/mm 3, respectively, in five control patients having no pain, a difference in proportion that was significant ( P = .027). Conclusions Patients in this study with verteporfin infusion-associated pain developed neutropenia during infusion, most likely from drug-induced neutrophil margination. It is possible that medications preventing the transient neutropenia may help avert verteporfin infusion-associated pain.

Pharmacokinetics and adverse effects of 20-mg/kg/day trimethoprim and 100-mg/kg/day sulfamethoxazole in healthy adult subjects

The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia (PCP). Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concentrations in serum and urine were measured by high-performance liquid chromatography. Five subjects withdrew from the study because of intolerable gastrointestinal and central nervous system toxicities. In the seven subjects that completed the study, the mean maximum serum drug concentrations after the last dose were 13.6 +/- 2.0, 372 +/- 64, and 50.1 +/- 10.9 micrograms/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 +/- 3.5, 14.0 +/- 2.3, and 18.6 +/- 4.3 h, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concentrations of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concentration-time curve (for all three parameters, r2 = 0.6 and P less than 0.05). Our findings add to the evidence that serum drug concentrations in adults following the conventional dose of trimethoprim-sulfamethoxazole for PCP are excessive and contribute to certain adverse reactions. Further studies are indicated in patients to optimize the dosing regimen of trimethoprim-sulfamethoxazole in the treatment of PCP.